BR112020011417A2 - compositions and methods for the treatment of metabolic conditions - Google Patents

Abstract

The present invention relates to stable therapeutic compositions of pharmaceutical grade acids and pharmaceutical grade pH buffering agents. The present invention is also directed to methods of treating mitochondrial disorders, metabolic conditions, diabetic conditions and cardiovascular conditions, by administering the compositions of the present disclosure.

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT OF CONDITIONS METABOLIC FIELD OF THE INVENTION

[001] The present invention relates to stable therapeutic compositions, comprising pharmaceutical grade acids and pH buffering agents. The present invention is also directed to methods of treating conditions and disorders characterized by mitochondrial disorder, metabolic conditions, diabetic conditions, cardiovascular conditions and bone and tissue modeling dysfunction, comprising administering compositions of the present disclosure.

BACKGROUND OF THE INVENTION

[002] Homeostasis is the ability of an organism to maintain a condition of balance or stability within its internal environment, particularly when faced with external exchanges. Some examples of homeostatically controlled systems in humans include the regulation of a constant body temperature, blood glucose levels, and extracellular concentrations of ionic species. Acid-base homeostasis refers to the proper balance of acids and bases in extracellular fluids, that is, the pH of the extracellular fluid. In humans, the pH of the plasma is approximately 7.4, and is held tightly around this value by three interconnected control systems: 1) buffering agents, including bicarbonate, phosphate, and proteins, 2) the respiratory system, which impacts the partial pressure of carbon dioxide in the blood plasma, and 3) the renal system, which excretes acids and residual bases. Acid homeostasis is also influenced by the metabolic load, which serves as a primary source of acid in the body. For example, a high glucose diet can increase the total acid load from metabolic sources, to put a greater load on the mechanisms of controlling acid homeostasis.

[003] Inefficiency in these control systems and factors, which increase acid, as well as metabolic sources, can gradually result in unstable internal means that increase the risk of disease, or exacerbate existing conditions. These inefficiencies can be caused by natural or self-inflicted aging processes through various lifestyle options. For example, a high glucose diet and a sedentary lifestyle can lead, over time, to the development of insulin insensitivity and type 2 diabetes. Diabetes is associated with other conditions, such as obesity, hypertension, hyperlipidemia, fatty liver, nephropathy, neuropathy, renal failure, retinopathy, diabetic ulcer, cataracts, insulin resistance syndrome, cachexia, diabetic foot ulcer and diabetic knee ulcer.

[004] Cardiovascular diseases can also be caused by a poor diet and sedentary lifestyle, and include coronary heart disease (heart attack), cerebrovascular disease, high blood pressure, (hypertension), peripheral arterial disease, rheumatic heart disease, illness congenital heart failure and heart failure. Such dysfunctional conditions of the heart, arteries and veins impair the oxygen supply to vital life-sustaining organs, including the brain and the heart itself.

[005] Heart attacks and strokes are mainly caused by a blockage in the inner walls of blood vessels that prevents blood from flowing to the heart or brain. Atherosclerosis (also called atherosclerosis) is a condition that involves excessive accumulation of fat or plaque deposits, respectively, which cause the veins that supply oxygenated blood to the tissues to narrow. In the arteries that serve the heart, for example, this can lead to ischemic heart disease, an obstruction of blood flow to the heart. Excessive accumulation of fat or plaque can also cause high blood pressure (hypertension), a disease known as "The Silent Killer", because the first warning sign is an attack of angina, a deadly heart attack or a stroke. Kidney disorders, obesity, diabetes, smoking, excessive alcohol, stress and problems with the thyroid and adrenal glands can also exacerbate a condition of high blood pressure.

[006] These conditions and many others are caused by inefficient, ineffective or under stress homeostatic processes. Over time, the resulting imbalance causes damage at the cellular and intracellular levels. Often the mechanisms for cell repair are so compromised that the cells cannot recover, or the mechanisms that cause the damage simply overwhelm the cells. the clinical significance of damage to living cells is manifested in a diseased cell, or symptoms of an underlying condition. It would be beneficial to develop methods to facilitate the inhibition of cell damage or to enhance recovery. The subject currently disclosed addresses, in whole or in part, these and other needs of the matter

SUMMARY OF THE INVENTION

[007] Therefore, it is an objective of the invention to provide solutions to the needs mentioned above.

[008] For this purpose, the present disclosure provides a stable therapeutic composition formulated for intravenous administration to an individual, comprising an intravenous buffer solution, comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffer agent in one sterile aqueous solution, characterized in that the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution are sufficient to provide a total titratable acid content of 60 mmol / l to 3000 mmol / l, when administered to an individual , and characterized in that the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent are effective in providing a buffer solution of pH between 4 and 7.7.

[009] In some embodiments, the pharmaceutical grade acid is hydrochloric acid, ascorbic acid, acetic acid, (other physiologically acceptable acids), or a combination thereof. In some embodiments, the at least one pH buffering agent is sodium bicarbonate, a phosphate, organic acid, organic amine, ammonia, citrate buffer, a synthetic buffer that creates specific alkaline conditions (for example, trishydroxymethyl amino methane)

(other physiologically acceptable buffers), or a combination thereof.

[0010] In some embodiments, the composition additionally comprises one or more ingredients selected from the group, consisting of vitamins, salts, acids, amino acids or salts thereof, and stabilized oxidizing species. In some embodiments, the composition additionally comprises ascorbic acid. In some embodiments, the composition comprises dehydroascorbic acid. In some embodiments, the composition comprises other recognized antioxidant defense compounds, including non-enzymatic compounds, such as tocopherol (aTCP), coenzyme Q10 (Q), cytochrome c (C) and glutathione (GSH), and enzymatic components including superoxide dismutase manganese (MnSOD), catalase (Cat), glutathione peroxidase (GPX), phospholipid hydroperoxide glutathione peroxidase (PGPX), glutathione reductase (GR); peroxiredoxins (PRX3 / 5), glutaredoxin (GRX2), thioredoxin (TRX2) and thioredoxin reductase (TRXR2). In some embodiments, the composition additionally comprises one or more of a sodium salt, a magnesium salt, a potassium salt, and a calcium salt. In some embodiments, the composition additionally comprises one or more of a vitamin B, vitamin C and vitamin K.

[0011] In some embodiments, the composition is formulated in hypotonic, isotonic or hypertonic form. In some embodiments, the composition is formulated for intravenous, bolus, dermal, oral, optical, suppository, buccal, ocular or inhalation administration. In some embodiments, the composition is formulated as a topical liquid, gel or paste. In some embodiments, the composition is formulated for eye administration in the form of eye drops. In some embodiments, the composition is freeze-dried or frozen. In some embodiments, the composition is stored in a spectral blocking vial. In some embodiments, the composition is formed by combining components from two or more vials.

[0012] In another aspect, the present disclosure provides a stable therapeutic composition formulated for intravenous administration to an individual, comprising pharmaceutical grade 900 t + 90 mg of L-ascorbic acid; 63.33 + 6.33 mg Thiamine HCl; 808 + 80.8 mg of magnesium sulfate; 1.93 + 0.193 mg of Cyanocobalamin; 119 + 11.9 mg of Niacinamide; 119 + 11.9 mg of Pyridoxine HCl; 2.53 + 0.253 mg Riboflavia 5S '"Phosphate; 2.93 + 0.293 mg Calcium D-Pantothenate; 840 + 84 mg Sodium Bicarbonate; 4.5 + 0.45 mM HCl; and water in an amount to obtain a final composition volume of ml In one embodiment of the invention, the composition additionally comprises 100 + 10 mg of dehydroascorbic acid.

[0013] In another aspect, the present disclosure provides a method of treating or ameliorating acidosis in an individual, the method comprising administering to the individual a stable therapeutic composition, comprising an intravenous buffer solution, comprising pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a sterile aqueous solution, characterized in that the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution are sufficient to provide a total titratable acid content of 60 to 3000 mmol / 1l , when administered to an individual, and characterized in that the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective in providing a buffer solution of pH between 4 and 7.7.

[0014] In yet another aspect, the present disclosure provides a method of treating or improving excess base in an individual, the method comprises administering to the individual a stable therapeutic composition, comprising an intravenous buffer solution comprising at least one grade acid pharmaceutical grade and at least one pharmaceutical grade pH buffering agent in a sterile aqueous solution, characterized in that the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution are sufficient to provide a total titratable acid content of 60 mmol / 1 to 3000 mmol / l1, when administered to an individual, and a method of raising blood oxygen in an individual, the method comprises administering to the individual the stable therapeutic composition, comprising an intravenous buffer solution, comprising at least a pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a sterile aqueous solution, ca characterized by the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution are sufficient to provide a total titratable acid content of 60 mmol / 1 to 3000 mmol / l, when administered to an individual, and characterized in that the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent are effective in providing a buffer solution of pH between 4 and 7.7. In one embodiment of the invention, the method comprises raising the pOr in venous blood in an individual.

[0015] Still in an additional aspect, the present disclosure provides a method of treating or ameliorating a mitochondrial disorder, metabolic disorder, a condition associated with diabetes or cardiovascular dysfunction in an individual in need thereof, the method comprises administering to the a stable therapeutic composition, comprising an intravenous buffer solution, comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffer agent in a sterile aqueous solution, characterized in that the concentration of the pharmaceutical grade acid and the buffer agent pharmaceutical grade pH in the buffer solution are sufficient to provide a total titratable acid content of 60 mmol / 1 to 3000 mmol / l, when administered to an individual, and characterized by the selection of pharmaceutical grade acid and the buffering agent of Pharmaceutical grade pH are effective in providing a buffer solution of pH between 4 and 7.7.

[0016] In some embodiments, the metabolic disorder is diabetes, insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia or hyperlipoproteinemia. In some embodiments, the condition associated with diabetes and hypertension, hyperlipidemia, fatty liver disease, nephropathy, neuropathy, renal failure, retinopathy, diabetic ulcer, cataracts, insulin resistance syndrome and cachexia. In some embodiments, cardiovascular dysfunction is coronary heart disease, cerebrovascular disease, hypertension, peripheral artery disease, occlusive arterial disease, angina, rheumatic heart disease, congenital heart disease, heart failure, heart failure, palpitations, supraventricular tachycardia, fibrillation, fainting, dizziness, fatigue, migraine, high levels of total blood cholesterol and / or LDL cholesterol, low level of HDL cholesterol, high level of lipoprotein, heart infections such as carditis and endocarditis, diabetic ulcer, thrombophlebitis, Raynaud's disease , anorexia nervosa, lameness, gangrene, atherosclerosis and peripheral artery disease. In some embodiments, the mitochondrial disorder is a neurodegenerative disorder, a cardiovascular disease, a metabolic syndrome, an autoimmune disease, a neurobehavioral or psychiatric disease, a gastrointestinal disorder, a stressful disease, a chronic musculoskeletal disease, or a chronic infection. In some embodiments, the eye condition is glaucoma, macular degeneration, floaters, stiffening of the eye lens or sensitivity to light.

[0017] In some embodiments, the composition additionally comprises dehydroascorbic acid. In some embodiments, the composition additionally comprises one or more sources of magnesium ions, a source of potassium ion, and a source of calcium ion. In some embodiments, the composition additionally comprises one or more of a vitamin B, vitamin C, and vitamin K. In some embodiments, the composition additionally comprises other recognized antioxidant defense compounds, including non-enzymatic compounds, such as tocopherol (aTCP), coenzyme Q10 (Q), cytochrome c (C) and glutathione (GSH), and enzyme components, including manganese superoxide dismutase (MnSOD - Manganese SuperOxide Dismutase), catalase (Cat), glutathione peroxidase (GPX), phospholipid glutathione peroxidase hydroperoxide (PGPX - Phospholipid Hydroperoxide Glutathione Peroxidase), glutathione reductase (GR); peroxiredoxins (PRX3 / 5) glutaredoxin (GRX2), thioredoxin (TRX2) and thioredoxin reductase (TRXR2).

[0018] In some embodiments, the composition is formulated in hypotonic, isotonic or hypertonic form. In some embodiments, the composition is administered intravenously, bolus, dermally, orally, optically, via suppository, buccally, ocularly or via inhalation.

[0019] In some embodiments, administration comprises introducing said composition by infusion over a period of about 1 minute to about 1 hour, and said infusion is repeated as needed for a selected time period of about 1 day about 1 year ago.

[0020] In another aspect, the present disclosure provides a method of modifying an individual's metabolism, the method comprising administering to the individual a stable therapeutic composition, comprising an intravenous buffer solution, comprising at least one pharmaceutical grade acid and at least a pharmaceutical grade pH buffering agent in a sterile aqueous solution, characterized in that the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution are sufficient to provide a total titratable acid content of 60 mmol / 1 to 3000 mmol / l, when administered to an individual, and characterized in that the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent are effective in providing a pH buffer solution between 4 and 7.7.

[0021] In another aspect, the present disclosure provides a method of treating a disorder of the central nervous system in an individual in need thereof, the method comprising administering to the individual a stable therapeutic composition, comprising an intravenous buffer solution, comprising at least at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent, in a sterile aqueous solution, characterized in that the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution are sufficient to provide a total titratable acid content of 60 mmol / 1 to 3000 mmol / l, when administered to an individual, and characterized in that the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent are effective in providing a pH buffer solution between 4 and 7.7.

[0022] In another aspect, the present disclosure provides a method of treating chronic injuries to an individual, the method "comprises administering to the individual a stable therapeutic composition, comprising an intravenous buffer solution, comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a sterile aqueous solution, characterized in that the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution are sufficient to provide a total titratable acid content of 60 mmol / la 3000 mmol / l, when administered to an individual, and characterized in that the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent are effective in providing a buffer solution of pH between 4 and 7.7.

[0023] In another aspect, the present disclosure provides a method of improving an individual's mental or physical performance, the method comprising administering to the individual a stable therapeutic composition, comprising - an intravenous buffer solution, comprising at least one grade acid pharmaceutical grade and at least one pharmaceutical grade pH buffering agent, in a sterile aqueous solution, characterized in that the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution are sufficient to provide a total titratable acid content 60 mmol / l to 3000 mmol / l, when administered to an individual, and characterized in that the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent are effective in providing a pH buffer solution between 4 and 7.7 .

[0024] In another aspect, the present disclosure provides a method for reducing an individual's lactate burden, the method — comprises understanding for administering to the individual a stable therapeutic composition, comprising an intravenous buffer solution, comprising at least one grade acid pharmaceutical grade and at least one pharmaceutical grade pH buffering agent, in a sterile aqueous solution, characterized in that the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution are sufficient to provide a total titratable acid content 60 mmol / l to 3000 mmol / l, when administered to an individual, and characterized in that the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent are effective in providing a pH buffer solution between 4 and 7.7 . In one embodiment of the invention, the lactate load is acidosis, sepsis, or multiple system atrophy (MAS - Multiple System Atrophy). In another embodiment, the lactate load is the result of physical effort.

[0025] In another aspect, the present disclosure provides a method for improving an individual's hypoxic stress, the method - comprising administering to the individual a stable therapeutic composition, comprising an intravenous buffer solution, comprising at least one pharmaceutical grade acid and at least at least one pharmaceutical grade pH buffering agent in a sterile aqueous solution, characterized in that the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution are sufficient to provide a total titratable acid content of 60 mmol / l to 3000 mmol / l, when administered to an individual, and characterized in that the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective in providing a pH buffer solution between 4 and 7.7.

[0026] In another aspect, the present disclosure provides a method for removing vascular plaque from an individual's arteries, the method comprising administering to the individual a stable therapeutic composition, comprising an intravenous buffer solution, comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent in a sterile aqueous solution, characterized in that the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution are sufficient to provide a total titratable acid content of 60 mmol / l to 3000 mmol / l1, when administered to an individual, and characterized in that the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent are effective in providing the pH buffer solution between 4 and 7.7.

[0027] In some embodiments of the invention, the method of the invention provides a buffer solution that is sufficient to reduce the physiological pH of an individual's bloodstream by 0.01 to 1.1. In other embodiments of the invention, the buffer solution is sufficient to reduce the physiological pH of an individual's bloodstream by 0.015 to 0.075. In other embodiments of the invention, the buffer solution is sufficient to reduce the physiological pH of an individual's bloodstream by 0.02 to 0.05. In other embodiments of the invention, the buffer solution is sufficient to reduce the physiological pH of an individual's bloodstream by 0.01 to 0.15. In other embodiments of the invention, the buffer solution is sufficient to reduce the physiological pH of an individual's bloodstream by 0.01 to 0.2. In other embodiments of the invention, the buffer solution is sufficient to reduce the physiological pH of an individual's bloodstream by 0.02 to 0.05. In other embodiments of the invention, the buffer solution has a buffering capacity sufficient to sustain the reduction in the physiological pH of the individual's bloodstream for between 1 minute and 1 week. In other embodiments of the invention, the buffer solution has a buffering capacity sufficient to sustain the reduction of the physiological pH of the individual's bloodstream for between 1 minute and 1 hour.

[0028] In one embodiment of any of the methods of the invention, the individual is a human or veterinary individual.

[0029] In another aspect, the present disclosure provides a kit, comprising (a) a first flask containing a stable therapeutic composition, comprising a buffer solution, comprising at least one pharmaceutical grade acid and at least one pH buffering agent of pharmaceutical grade, characterized in that the buffer solution is sufficient to reduce the physiological pH of an individual's bloodstream by 0.1 to 1.1, and characterized in that the buffer solution has a buffering capacity sufficient to sustain the reduction of the physiological pH of the blood flow of the individual for between 1 minute and 1 week; and (b) instructions for use.

[0030] In another aspect, the present disclosure provides the kit, comprising (a) a first vial containing an intravenous buffer solution, comprising at least one pharmaceutical grade acid in a sterile aqueous solution; (b) a second vial containing at least one pharmaceutical grade pH buffering agent in a sterile aqueous solution, characterized in that, when combined, the contents of the two vials form an intravenous buffer solution, characterized by the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of 60 mmol / l to 3000 mmol / l, when administered to an individual, and characterized by the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agents are effective to provide a pH buffer solution between 4 and 7.7; and (c) instructions for use.

[0031] Details of one or more embodiments of the invention are presented in the description below. Other characteristics, objectives and advantages of the invention will be evident from the description and the claims.

BRIEF DESCRIPTION OF THE FIGURES

[0032] The accompanying drawings, which are incorporated into this document and form part of this specification, illustrate currently preferred embodiments of the invention, and, together with the general description described above and the detailed description below, serve to explain the characteristics of the invention. In the drawings:

[0033] Figure 1 represents a diagram of the typical chemosmotic gradient of hydrogen ions between the inner membrane and matrix in a mitochondria, which normally functions in a mammalian cell.

[0034] Figure 2 represents a diagram of the reduced chemosmotic gradient of hydrogen ions in a mitochondria in a mammalian cell with a dysfunctional metabolism, such as. it can occur after prolonged exposure to a poor diet, or lack of exercise.

[0035] Figure 3 represents a diagram of the chemosmotic flow of ions inside and outside the cell of an individual having a hypoxic crisis, or as seen in phases of acid-base disorders, such as during or after exercise, or as observed during or after using the composition of the invention.

[0036] Figure 4 represents a diagram of the chemosmotic flow of ions inside and outside the cell of an individual who had the hypoxic crisis corrected by using the composition of the invention.

[0037] Figure 5 shows a diagram of the amplitude and duration of an acid state change caused by different formulations of compositions of the present disclosure.

[0038] Figures 6, 7, 8, 9, 10 and 11 show a graphical representation of the pH and HCO response; (Figure 6 - Composition of acid change; Dose 1, DAY 1); response sO>, pCcOr, por (Figure 7 - Acid Shifting Composition; Dose 1, Day 1); pH and HCO3z "response (Figure 8 -—- Acid change composition with Vitamins and Minerals; Dose 4, Day 6); sO2, pCOr, pOr response (Figure 9 - Acid change composition with Vitamins and Minerals; Dose 4 , Day 6); pH and HCO response; (Figures 10 —- Composition of acid change with Vitamins and Minerals; Dose 5, Day 8); and response sOx, pCO2, pOr (Figure 11 - Composition of acid change with Vitamins and Minerals;

Dose 5, Day 8) of Individual 2, after administration of the therapeutic composition.

[0039] Figures 12 and 13 show a graphical representation of the pH and HCO response; (Figure 12 - Composition of acid change; Dose 1, Day 8); and response of sO, x, pCO>, pOr (Figure 13 - Composition of acid change; Dose 1, Day 8) of Individual 3, after administration of the therapeutic composition.

DETAILED DESCRIPTION OF THE INVENTION

[0040] The present invention will now be described in more detail in this document. However, many modifications and other embodiments of the present invention set out in this document, for example, for the improvement and / or treatment of specific conditions and disease states, will be remembered by an expert in the field to which the invention belongs, having the benefits of teachings presented in the previous descriptions. Therefore, it will be understood that the present invention will not be limited to the specific embodiments disclosed and these modifications and other embodiments are intended to be included within the scope of the appended claims.

[0041] As used in this document, the term "mammal" refers to humans as much as all other mammalian animals. As used in this document, the term "mammal" includes an "individual" or "patient" and refers to a warm-blooded animal. It is understood that guinea pigs, dogs, cats, rats, mice, horses, goats, cattle, sheep, zoo animals, domestic animals, primates and humans are also examples of animals within the scope of the term's meaning. As used in this document, "a mammal in need of it" may be an individual that it could have been, but it is not necessary that it has been diagnosed as suffering from the condition that it is intended to treat. In one aspect, the present method is aimed at conditions that are perceptible to the individual and the individual wishes to treat or improve the condition without a formal diagnosis. Alternatively, a mammal in need of it is one that has been diagnosed as having a condition and is in need of specific treatment. In other embodiments, a mammal may also be functioning normally in relation to common standards, but positively seek to improve performance for various purposes, such as for greater mental acuity or athletic interests.

[0042] The terms "individual" and "patient" are used interchangeably, and are intended to refer to any mammal, including humans, that has, or is at risk of developing a dysfunctional cardiovascular condition. The individual or patient is typically human, however, other suitable individuals or patients include, but are not limited to: laboratory animals, such as mice, rats, rabbits, or guinea pigs, farm animals and domestic animals or pets. pet. Non-human primates are also included.

[0043] As used in this document, the "therapeutically effective amount" is an amount effective to elicit a cellular response that is clinically significant.

[0044] As used in this document, the terms "treat" and "improve" are intended to refer to all processes characterized by a delay, interruption, repression, or halt in the progression of the condition or symptoms, and does not necessarily indicate a total elimination of the underlying condition. The terms also encompass the administration of a pharmaceutical grade, physiological component, or natural physiological buffer composition characterized by the mammal having a condition or symptom or a predisposition to a condition or symptom, in which the objective is to heal, improve, alleviate, mitigate , change, improve or affect the condition or symptom or the predisposition to it. It is also contemplated as preventing the condition or symptom, or predisposition to it, by prophylactically administering a pharmaceutical grade buffer composition as described in this document.

[0045] As used in this document, the term “pharmaceutical grade” means that certain biologically active and / or inactive components specified in the drug must be within certain specific absolute and / or relative limits of concentration, purity and / or toxicity and / or that components must exhibit certain levels of activity, as measured by a given bioactivity test. In addition, a “pharmaceutical grade compound” includes any active or inactive drug, biological or reagent, for which a standard of chemical purity has been established by a recognized national or regional pharmacopeia (for example, US Pharmacopeia (USP), British Pharmacopeia (BP), National Formulary (NF), European

Pharmacopoeia (EP), Japanese Pharmacopeia (JP), etc.). the pharmaceutical grade also incorporates suitability for administration by means that include topical, ocular, parenteral, nasal, pulmonary tract, mucosa, vagina, rectal, intravenous and the like.

[0046] The present disclosure is based on the unexpected revelation that reducing the physiological pH of the bloodstream in an individual is useful in the treatment, for improvement, and prevention of many conditions and diseases and symptoms of the same in an individual in need. The invention provides a stable therapeutic composition, which can be administered to an individual in need, in order to provide the required change in blood pH.

[0047] Figure 1 represents a diagram of the potential chemosmotic gradient of hydrogen ions in a mitochondria, functioning normally in a mammalian cell. As shown in this document, blood and interstitial fluid typically have a pH around 7.4, the intracellular fluid within the cell has a pH around 7.28, and the mitochondrial space within a cell has a pH in around 6.88. Ion pumps concentrate H * ions in the intermembrane space of the mitochondria, resulting in a large gradient of H * between the intermembrane space and the mitochondrial matrix across the inner membrane. The concentrations of other ionic species, such as Caº *, Na ', K', Mgº ”, and Cl” are also manipulated to create an electrochemical gradient across the various membranes, and Ca? ” intramitochondrial in particular is important to manage the flow of H 'ions within the mitochondria. Hydrogen ions flow through the inner membrane in the mitochondrial matrix through ATP synthesis, creating ATP from ADP. The electron transport chain is used to pump H + Ion ions back through the inner membrane to maintain the proton gradient. A small percentage of electron transfer occurs directly in oxygen, leading to the formation of free radicals, which contributes to oxidative stress and can result in damage to the membrane if there are insufficient antioxidants.

[0048] Figure 2 represents a diagram of the potential for chemosmotic gradient of hydrogen ions in a mitochondria in a mammalian cell with a dysfunctional metabolism, as can occur after prolonged exposure to a poor diet, or lack of exercise. As shown in Figure 2, blood, interstitial space, and intracellular fluid undergo acidic changes, that is, increased the concentration of H + ions and reduced the pH. At the same time, the pH in the mitochondrial matrix increases from its normal, due to the leak in the membrane or the reduced pumping action of H + ions from the electron chain transport. As a result, the H * liquid electrochemical gradient for the formation of ATP is reduced. In addition, the cell and mitochondria must increasingly depend on other ionic species to provide the necessary electrochemical gradient, such as through higher than normal concentrations of ca? inside the intermembrane space, "pushing" hydrogen ions across the inner membrane and a higher concentration of Cl "within the mitochondrial matrix," pulling "the hydrogen ions. This dysfunctional ionic balance results in greater development of superoxidative species and increased damage to the membrane, and the cell's metabolism slows down as a consequence. This reduces the amount of ATP available, causing a feedback loop, which is negatively reinforced and can lead to various adverse conditions and disturbances.

[0049] A similar metabolic dysfunction occurs as a result of poor perfusion, leading to a lactate load, called metabolic acidosis in statochronic, which can be caused, for example, sepsis, multiple system atrophy (MAS), and ischemic conditions in the peripheral limbs. For individuals suffering from a chronic lactate load, high blood lactate levels constantly shift bicarbonate buffers to maintain acid-base homeostasis. A fraction of bicarbonate can be removed by kidney action to maintain homeostasis and to reduce bicarbonate levels in the bloodstream. In addition, chronic electrolyte disturbances can alter the bicarbonate retention setpoint to further reduce stocks. Such forces, in turn, would make less bicarbonate accessible for intracellular retention and intracellular buffer, ultimately reducing H 'intracellular reserves. This reduction in H * reserves would require May Caº ”** to sustain the desired chemosmotic gradient, leading to a dysfunctional ionic balance as described above.

[0050] The stable therapeutic compositions of the present disclosure reduce the physiological pH of the bloodstream in an individual, and maintain that decrease in the physiological pH of the bloodstream for a period of time, until the renal and respiratory compensation processes cancel the reduction, commonly followed by alkaline "recovery". The compositions of the present disclosure are formulated, so that the formulated pH is below the physiological norm (i.e., below 7.4). The bicarbonate concentration may, in some cases, be above the physiological norm (that is, above 29 mM). The sudden influx of H + ions, together with the excess of bicarbonate, and the manipulation of the resulting electrochemical gradient, allow the return to normal mitochondrial metabolic processes, while other electrolytes, vitamins and antioxidants present in the compositions of the present disclosure reduce damage by oxidative stress . Other benefits of administering compositions of the present disclosure include improvement of at least one of the cardiovascular conditions, vessel dilation, wound healing, vascular plaque, maintenance of bicarbonate, electrolyte savings, metabolic dysfunction, oxygen deficiency, Citric Acid Cycle, operation renal system, antioxidant dysfunction, angiogenesis, nitric acid (NO - nitric oxide) dysfunction, hormonal function and anemia.

[0051] In one embodiment of the invention, the compositions of the present invention are suitable for improving cardiovascular conditions by reducing or removing vascular plaques. Plaque forms in the arteries as a result of several factors, which are rooted in an injury-related signal dysfunction, including for example, lipid dysfunction, nitric oxide dysfunction and excessive ROS, which are caused, in part, by the presence of a acidic environment in cells.

For example, in an acidic environment, exogenous ROS levels are elevated.

Smooth muscle contains several sources of ROS, which have been shown to function as important signaling molecules in the cardiovascular system.

The elevated ROS signals that the smooth muscles accumulate in the arteries, as if they were recruited to fill in lesions that do not actually exist.

In addition, in an acidic environment with ROS and the absence of nitric oxide, macrophages are signaled to respond to a non-existent threat, causing them to convert from Ml to M2, and initiate the sequestration of lipids.

Fat-laden lipids become accumulations of foam cells.

In addition, in an acidic environment, there is a dysfunction in the endothelial synthesis of nitric oxide (eNOS - endothelial Nitric Oxide Synthase), causing a greater availability of arginase, which is necessary for the synthesis of collagen, and therefore, works with the action stimulated by acidic pH of fibroblasts to promote an accumulation of collagen in the arteries.

Elevations of intracellular Ca? ** retention, and increases in unbound phosphates that occur in metabolic dysfunction associated with an acidic environment (because less phosphate is complexed with ADP to form ATP), result in the promotion of calcified mineralized components of the plates.

By restoring an alkaline environment in the cells, the compositions of the invention are able to reduce or reverse the vascular plaque by correcting or improving at least one of: nitric oxide dysfunction (thus restoring NO signaling), lipid dysfunction, eNOS dysfunction, reduction in smooth muscle recruitment, reduction of reactive endogenous and exogenous oxygen species (ROS - Reactive Oxygen Species), Ca? ” elevation or restoration of fatty acid metabolism. For example, after the introduction of an alkaline environment, smooth muscles, in the absence of the ROS signal, recognize the absence of an injury, and consequently, they regulate negatively, and begin to orient themselves towards their vasodilation and vasoconstriction tasks. . In addition, for example, in an alkaline environment, low ROS in the presence of eNOS nitric oxide signaling, foam cells are signaled to release their lipids. Along with reversal or reduction of the calcified plaque, the elasticity of the vascular vessel returns. In addition, the action of the drug's acid change releases atomic components from the mineral deposits, while the magnesium in the composition of the invention helps prevent plaque redeposition to reduce the hardening of the arteries of the mineral deposit components.

[0052] In one embodiment of the invention, the compositions of the present invention are suitable for preventing or minimizing hypoxia in an individual. The lack of sufficient oxygen that reaches cells or tissues in an individual can occur even when blood flow is normal. This can cause many serious, sometimes life-threatening complications. Use of the compositions of the invention allows the resolution or amelioration of conditions commonly associated with hypoxia, such as, for example, heart attack, cardiovascular problems, lung conditions, concussion cascade, reperfusion injury, myocardial infarction, hypoxia associated with diabetes, tissue trauma, and the like, many of which are associated with vasoconstriction.

The composition can neutralize such vasoconstriction, promoting vasodilation via at least one of the three routes, namely endothelin, prostacyclin, or NO-soluble guanylyl cyclase (NO-SGC - NO-soluble Guanylyl Cyclase). For the endothelin route, the compositions elevate the Mg ”in the bloodstream to antagonize Ca”. This blocks the Ca ”from potentiating vasoconstriction, allowing the arteries to relax and dilate.

Meanwhile, the compositions also provide metabolic corrections to reduce the metabolic sources of ROS, and to reduce the production of endothelin stimulants on the cell surface, thereby reversing the Ca? * Over-stimulation. For the prostacyclin route, niacinamide in the composition increases the activity of cyclic adenosine monophosphate 3 ', 5' (CAMP - cyclic Adenosine MonoPhosphate), which completes the potentiation of prostacyclin in relation to vasodilation.

For the NO-sGC pathway, as noted above, the compositions of the invention provide an H * gradient that flows in the cells to promote Caº * 'efflux, which corrects high Ca? Production. ” An effect of high levels of Ca? is the elevation of the caveolina.

As the caveolin rises, they reside in the cavolae on the cell surface, causing the displacement of eNOS, which migrates to the Golgi system.

The combination of low ROS and low intracellular Ca? ** achieved using the composition of the invention, allows eNOS to return from the Golgi to the cell membrane, thereby restoring eNOS's ability to promote vasodilation.

As eNOS returns to the membrane, the pH of the bloodstream changes, promoting the release of NO via the NO-

sGC and promoting vasodilation. In addition, renal responses to pH rebalancing produce a second “change in pH” towards alkaline, once again stimulating NO / NO-sGC vasodilation to prolong the duration of the effect.

[0053] As shown in Figure 3, when an individual's body is in a state of metabolic crisis, such as a hypoxic crisis, intracellular acidification drives the intracellular accumulation of Ca *. This is because it is necessary to use adenosine triphosphate (ATP - Adenosine TriPhosphate) to resolve the sodium charge created as H * leaves cells. However, in the hypoxic state, ATP is impaired, and as a consequence, the Na '/ K' ATPase pump becomes inactive. The exchange of Caº * / Na * should solve the Na ”charge, accumulating Ca? ** in the cell. To reverse this process, the hypoxic state must be resolved to restore the production of ATP (and Na '/ K ”ATPase), or extracellular H * must be produced. As shown in Figure 4, the compositions of the invention achieve both, allowing rapid resolution of Ca? ** overload and the corresponding metabolic crisis. The composition adjusts the pH of the bloodstream, acidifying it, and in doing so, causes H * to enter the Na '/ H' exchange route. As H 'enters, it pushes O Na "out. As noted above, the composition of the invention promotes vasodilation of the vessels to improve blood flow. With this increase in blood flow, oxygen intake begins to increase, the which allows the creation of ATP through aerobic metabolism. The composition also elevates Mg? ** in the bloodstream. The increase in Mg? facilitates the transport of ATP, such as Mg-ATP, to Na '/ K' ATPase, providing the stimulus to push Na 'out. Part of the increase in Na * in the bloodstream enters again by the exchange of Ca ”/ Na'. Additionally, the presentation of H * in the bloodstream, together with elevated bicarbonate in the bloodstream, promotes the entry of bicarbonate into the cell. This process provides an antidote to reverse the accumulation of calcium in the cell, improving the cells' ability to restore a chemosmotic gradient with less Caº dependence ** and more H * buffered H * usefulness for finally reduced r the metabolic acid load and the metabolic ROS, to promote the restoration of the intracellular towards the alkaline, with improvement of the redox condition. Tight polarization through alkaline and low ROS promotes positive electrolyte and pH rebalancing in the cytosol, organelles, lysosomes, peroxisomes, calcium condition, magnesium condition, ROS condition within the cell. Additionally, it alters cell economics to restore potassium and bicarbonate, while at the same time reducing intracellular calcium.

[0054] The vasodilation that can be achieved by using the composition of the invention makes the composition useful for treating injuries. It has been unexpectedly found that the use of the compositions of the invention can provide recovery in individuals in whom conventional treatment methods have been exhausted, including those with gangrenous presentation, or chronic diabetics, or traumatic injuries Metabolic changes are among the effects seen after traumatic injury and surgical trauma. This includes inflammatory responses, which trigger a blood flow constriction in the affected regions. Although this advantageously reduces blood loss at the site of an open lesion or internal bleeding, it can impair healing by promoting a hypoxic intracellular environment. In trauma situations where the risk of bleeding is absent Or reduced (for example by compression), it may be desired to suppress the inflammatory response, to avoid secondary hypoxia injuries. In cases of chronic inflammation, such as with critical chronic limb ischemia (CLI - Chronic Limb Ischemia), suppression of inflammation can accelerate healing. The promotion of vasodilation and the improvement of perfusion caused by the composition of the invention helps to interrupt the inflammatory cycle. In addition, promoting vasodilation, in order to increase oxygen maintenance, the compositions of the invention are also capable of correcting the main metabolic aberrations that are present in the lesions. The compositions can, for example, improve at least one of the conditions of restoration of the acid buffer and correction of high Caº *; reducing ROS from metabolic sources; correction of acidosis; correction of hyper active iNOS and restoration of eNOS and nNOS function; promotion of beneficial angiogenesis after correction of eNOS; and iNOS suppression promotes aberrant angiogenesis, all of which are important for the treatment of injuries.

[0055] As H also manages the uptake of acetylcholine, which is part of the muscle support, and is a part of the cerebellum control process, and ATAT is relevant to all of these systems, central nervous system disorders are another target of treatment. Additionally, the action to resolve intracellular acid, calcium accumulation, ROS reduction and Mg increase, are factors that can improve the function in the peroxisome, to better maintain the supply of catalase antioxidants, and additionally support the lipid modeling necessary for the maintenance of myelin in the nerve sheaths.

[0056] In some cases, the reduction in the physiological pH of the bloodstream caused by the composition of the invention may be minimal, or not observed, due to the particular formulation of an administered composition, the reason why a composition is administered, or both. However, the therapeutic benefits described in this document can still be achieved due to the net rise in the concentration of bicarbonate that occurs. Due to an excess of H in administration, the body prioritizes the retention and increase of buffer components (for example, bicarbonate), as the acid balance processes proceed. Thus, a larger fraction of the buffering agent is retained within the cells and in the bloodstream as the system alkalinizes and returns the physiological pH to the baseline. Such "alkaline recovery" can result in an excessive increase in the pH of the bloodstream for a liquid alkaline stabilization in relation to the initial pH. "Alkaline recovery" achieves a higher residual concentration of intercellular buffer components and the bloodstream, including bicarbonate. Alternatively, the system can regulate to a final pH equivalent to that present before treatment, but with bloodstream buffering, relative to to acidic species, as it is increased. Alternatively, the pH of the bloodstream may become more acidic than before treatment, although a variety of the above mentioned exchange phenomena are still promoted. Unlike the infusion of a simple tampon, such as bicarbonate, in the absence of acidic components, co-administration of acid and buffer is essential to limit the H 'efflux rate, while intracellular calcium correction is achieved.

[0057] In one embodiment of the invention, the compositions of the present invention are suitable for enhancing nitric oxide synthesis (NOS - Nitric Oxide Synthase) in an individual. Polarization of pH and increase in bicarbonate concentration, as provided by the compositions of the present disclosure (including reductions in pH after administration and "alkaline recovery" as homeostasis is restored) can also restore endothelial and neuronal NOS, leading to an increase selective in the production of nitric oxide. Nitric oxide is a gas signaling molecule with a role, for example, homostasis, smooth muscle (particularly surrounding vasculature), neuronal and gastrointestinal signaling. NO is implicated in a variety of physiological systems, and the increased levels resulting from the administration of the compositions described in this document may play a role in providing the therapeutic benefits described in this document. For example, in glaucoma, NO can play a role in regulating intraocular pressure through the trabecular meshwork. In atherosclerotic plaques, NO interrupts the aberrant perpetuation of smooth muscle recruitment, accumulation of foam cells and lipid storage, and collagen deposition and can ultimately lead to the reversal of plaque damage and the return of vascular section to physiological norms.

[0058] In one embodiment of the invention, the compositions of the present invention are suitable for reducing the lactate burden on an individual in need thereof. As used in this document, the term "lactate load" means any physiological condition characterized by elevated lactate levels. This may include, for example and without limitation, chronic lactate loads, such as acidosis, sepsis, and MSA, or acute lactate loads, as may occur during and after physical exertion, such as exercise. The load of the lack of circulating oxygen in the lactate that is retained in the muscles, can be stimulated to be released by the bicarbonate, and subsequently metabolized, thus reducing the individual's lactate load. The ability to eliminate the lactate load is important for an individual who has had, for example, an organ transplant. Where the transplant procedure involves the use of citrate anticoagulants, citrate must be metabolized. This metabolism can induce a lactate load in these individuals. Additionally, the lactate load is a component of sepsis and a chronic load in diabetics. In the above cases, as well as in others involving a lactate load, the use of the compositions of the invention can reduce that load.

[0059] In one embodiment of the invention, the compositions of the present invention are suitable for reducing acidosis in an individual in need thereof, by administering to the individual the composition of the invention.

One of the metabolic effects of trauma is the suppression of insulin, resulting in a reduction in the normal anabolic effect of insulin in the direction of an increase in the catabolic effect.

This leads to a change in free fatty acids as the main source of energy, with triglycerides providing 50 to 80% of the energy requirement.

Reducing the catabolic response allows for faster healing after surgery.

These same mechanisms are at play in the diabetic patient, and it becomes a greater challenge as individuals progress in their metabolic dysfunction.

Underlying this catabolic process are aberrations in the metabolic chain that tend to incomplete oxidation, leading to an increase in acidic products and an increase in ROS from metabolic sources.

As noted in this document above, in trauma, this catabolic change is driven by the hypoxic state, as inflammation and the vasoconstrictor response impair circulation.

In diabetes, the change is marked by glucose intolerance, and is aggravated by plaque-induced circulatory disorders and a sedentary lifestyle.

In both cases, incomplete oxidation results in acidification in the cell and in promoting transport predisposition that causes Ca? ** to be concentrated in the cytosol.

That concentration of Ca ”cascade into the inner mitochondrial membrane, so that Ca? assume a greater role in the chemosmotic gradient, reducing the role of H 'itself. This change in Ca? ” and H 'initiates a progressive shutdown (ECT), so that Ca ”* assumes a greater role in controlling the chemosmotic potential. This also leads to an increase in metabolic ROS from the stages of ECT. Over time, impaired circulation reduces the maintenance of vitamin B, which impairs both Krebs cycles and ECT, further increasing metabolic ROS. At the same time, impaired circulatory service reduces antioxidant maintenance, allowing for elevation in uncontrolled ROS. Although these aberrations have beneficial qualities, such as promoting the creation of NAPDH oxidases for bactericidal function during infection, they also compromise the healing process, as they promote catabolism. In addition, a balance of signals, including acidosis, hypoxia, Ca? *, ROS and iNOS / NO, collectively suppress the emergence of M2 macrophages, as desired, to promote healing. To address these aberrations, the composition of the invention facilitates the correction of Caº * ', and improves the maintenance of vitamin B and the maintenance of the ascorbic acid anti-oxidant through the elevated presentation. Additionally, the acid load is reduced, promoting an alkaline tendency. High levels of HCO3 "t buffer also serve to preserve these alkaline trends.

[0060] The metabolism elements mentioned above also affect insulin control. For example, insulin release is stimulated from the pancreas when an elevated Caº * 'signal is released into the bloodstream. Why Ca? is released into the pancreas, the hydrogens must be created through incomplete metabolism, to move Caº ”from the cytosol into the bloodstream. As noted above in this document, Na '/ K

ATPase should be served with Mg? ** and ATP to facilitate flooding of Na * into the bloodstream to finally stimulate the alteration of Nat / Ca ** to release Ca? ** into the bloodstream. Additionally, for the elevation to be detected, the background level of Ca ** in the bloodstream needs to be low enough for the pancreas to observe the change. In acidosis, this would be impaired, as the solubility of Caº ”** is high in blood and cytosol. As an additional example, ROS, such as peroxides, can promote insulin function, when presented at low levels, and prevent the presentation and action of insulin, when presented at high levels. Thus, correcting acidosis and increasing Mg? ** are essential to restore insulin control. The same happens with the suppression of ROS (for example, H202) through the antioxidant support and facilitation of the TCA and ECT function to obtain an almost complete oxidation of Acetyl-CoA in CO; and H2O. Compositions

[0061] In one embodiment of the invention, the composition of the invention is a stable therapeutic composition that has been formulated to make it suitable for intravenous administration in an individual. The composition contains an intravenous buffer solution, containing at least one pharmaceutical grade acid, and at least one pharmaceutical grade pH buffering agent. To ensure their suitability for pharmaceutical use, acidic solution and buffer are present in a sterile aqueous solution. The concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of 60 mmol / l to 3000 mmol / l when administered to an individual. The acid and base are selected so that they can together be able to provide a buffer solution, having a pH of between 4 and 7.7.

[0062] In one embodiment of the invention, the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of 80 mmol / 1 to 3000 mmol / l1, when administered to an individual, where the buffer solution is effective in providing a buffer solution of pH less than 5.5. In another embodiment of the invention, the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of 100 mmol / 1 to 2000 mmol / l1, when administered to an individual , where the buffer solution is effective to provide a buffer solution of pH less than 5.5. In an embodiment of the invention, the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of 200 mmol / 1 to 1000 mmol / 1, when administered to an individual, wherein the buffer solution is effective to provide a buffer solution of pH less than 5.5.

[0063] In one embodiment of the invention, the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of 40 mmol / l1 to 3000 mmol / 1, when administered to an individual, in which the buffer solution is effective to provide a buffer solution of pH of less than, greater than or equal to 5, 5. In another embodiment of the invention, the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of 60 mmol / 1 to 2000 mmol / 1, when administered to a individual, where the buffer solution is effective to provide a buffer solution of pH less than, greater than or equal to 5.5. In embodiment of the invention, the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acid content of 80 mmol / l to 3000 mmol / l, when administered to an individual, in that the buffer solution is effective to provide a buffer solution with a pH lower than, greater than or equal to 5.5.

[0064] An acid is a molecule or ion that is capable of donating an H * hydrogen ion. The amount of H + ions in a solution is measured by its pH, where a pH below 7 is an acidic pH. Human beings typically have a pH in the bloodstream of 7.4. The compositions of the present disclosure comprise an acid that provides an amount of H + ions to lower the physiological pH of the bloodstream in an individual. Without being bound by any theory, it is believed that the compositions of the present disclosure increase the H 'gradient in various cellular environments, including, for example, mitochondria. This increase in the H * mitochondrial gradient generates greater ATP production and, through other physiological homeostatic systems, causes changes in the concentration gradient of cell membranes, which in turn rebalances physiological ions, such as sodium, magnesium, potassium and calcium. For example, can an increase in the H 'gradient in the bloodstream stimulate calcium pumps in cell membranes, thereby increasing intracellular H' and reducing Ca? ” intracellular. Gradients of sodium, magnesium and potassium concentration are also affected. By manipulating the ionic gradients using the compositions of the present disclosure, many conditions and diseases and symptoms thereof can be treated, improved or prevented.

[0065] In some embodiments, compositions of the present disclosure are sufficient to reduce the pH of an individual's bloodstream by a small, moderate or large amount. In some embodiments, the amount of acid in a composition of the present disclosure is sufficient to reduce the pH of an individual's bloodstream by 0.01, 0.02, 0.03, 0.04, 0.05, 0.06 , 0.07, 0.08, 0.09, O, 1, 0.15, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 , 1.0, or 1.1, or more. The reduction in pH can also be expressed by the desired pH level of the bloodstream after administration of a composition of the present disclosure, for example, 7.2. In some embodiments, a composition of the present disclosure comprises acid to reduce the pH of an individual's bloodstream to 7.3, 7.2, 7.1, 7.0, 6.9, 6.8, 6.7, 6.6, 6.5, 6.4, or 6.3. Normally, a reduction in the pH of the bloodstream below 6.3 is not recommended, as it can pose a risk to cell health and threaten the integrity of the cell phospholipid bilayers. In cases of alkalosis where the nominal pH can exceed 7.4, an

“Reduction” in the pH provided by the administration may still result in a pH in the bloodstream greater than 7.4. For example, administration of a composition of the present disclosure can change the physiological pH from 7.7 to 7.5.

[0066] The compositions of the present disclosure may contain one or more pharmaceutical grade acids. In some embodiments, the compositions of the present disclosure comprise a mixture of one or more acids of a pharmaceutical grade. The acids can include any acceptable physiological acid, including, without limitation, hydrochloric acid, ascorbic acid, citric acid, lactic acid, phosphoric acid, or combinations thereof. The pH of a composition of the present disclosure can be between about 4 and 7.7. In some embodiments, the pH of a composition of the present disclosure is between about 6.1. In embodiments where the pH of the composition is very low, it may be necessary to manage the administration rate to avoid damage to tissues adjacent to the injection site, as the dilution is carried out in the bloodstream.

In another aspect, the compositions of the present disclosure comprise a pH buffering agent. A pH buffering agent is a weak acid or base that is used to keep the pH of a solution close to a desired value. The compositions of the present disclosure comprise a pH buffering agent, so that the reduction in the pH of the blood stream can be sustained for a desired duration. In some embodiments, the pH buffering agent may comprise a conjugated acid or a conjugated base. In some embodiments, the pH buffering agent may comprise any physiological acceptable buffering agent, including, without limitation, sodium bicarbonate, a phosphate buffer, citrate buffer, or a synthetic buffer that creates specific alkaline conditions (e.g. hydroxymethyl amino methane), or combinations thereof.

[0068] The buffering capacity of a solution is a measure of the solution's ability to resist pH change, that is, to maintain a specific pH level. As discussed above, acid-base homeostasis refers to the proper balance of acids and bases in extracellular fluids, that is, the pH of the extracellular fluid. In humans, the pH of the plasma is approximately 7.4 and is strongly maintained around this value by three interconnected systems: 1) buffered agents, including bicarbonate, phosphate and proteins), 2) the respiratory system, which affects partial pressure of carbon dioxide in the blood plasma, and 3) the renal system, which excretes acids and residual bases. Therefore, in some embodiments, the compositions of the present disclosure comprise a pH buffering agent, in order to maintain the desired pH level of the bloodstream below the typical pH value of about 7.4 in view of the pressures exerted by the systems physiological factors that regulate acid-base homeostasis. In some embodiments, the compositions of the present disclosure comprise a pH buffering agent in an amount sufficient to maintain the pH reduction in the bloodstream, or to maintain the desired pH level, for a period of 1 minute to 1 week.

[0069] The desired duration of the reduced pH level in the bloodstream will depend on the particular indication to be treated as well as the individual to be treated. In some embodiments, an ability to buffer small, moderate or large may be desired. In a medium of administration, a small amount of drug and / or a slow administration of a drug can stimulate compensatory processes that can be respiratory or renal, in order to mitigate an observable potential for acid change, but having stimulated respiratory and renal activity . In such cases, a bloodstream response may be neutral or may tend to be alkaline. Alternatively, the administration of a high dose and / or a dose with a rapid rate of administration, such as a bolus or rapid IV drip can introduce the acid and overload the compensatory processes to produce a subsequent observable pH for acid. Normally, this stimulus is expected to be followed by a recovery of pH throughout the treatment or after treatment. The outcome results for a given dose level and / or administration rate may differ from patient to patient and from administration to administration, as the patient's health, electrolyte status, pH status and state of the compensatory process evolve . Different buffering capabilities may be sufficient to maintain the pH reduction in the bloodstream for a duration of 1 minute to 1 week. In other embodiments, the buffering ability can also be expressed in the molar equivalent of common buffers, such as bicarbonate.

[0070] In some embodiments, the composition has a buffering capacity between 0.1 mM HCO3 "equivalent and 1200 mM HCO3" equivalent. In other embodiments, the buffering capacity is between 0.1 mM HCO3 "equivalent and 10 mM HCO3" "equivalent. In some embodiments, the buffering capacity is between 10 mM HCO3 equivalent and 50 mM HCO3" equivalent. In some embodiments, the buffering capacity is between 10 mM HCO3z "equivalent and 1000 mM HCO3" "equivalent. In some embodiments, the buffering capacity is between 50 mM HCO3 "" equivalent and 800 mM HCO; 3 "equivalent. In some embodiments, the buffering capacity is between 100 mM HCO; equivalent and 600 mM HCO; equivalent. In some embodiments, the buffering capacity is between 200 mM HCO; equivalent and 550 mM HCO3 "" equivalent. In some embodiments, the buffering capacity is between 20 mM HCO3 "equivalent and 100 mM HCO3" equivalent. In other embodiments, the buffering capacity can be expressed by the molar concentration of HCO;, or other common buffers, for example, in some embodiments, the molar concentration of HCO; may be between 0.01 molar and 10 M. In other embodiments, the molar concentration of HCO; may be between 0.5 and 2 M.

[0071] In another embodiment, the present disclosure provides a composition having a pH below the physiological pH (i.e., below 7.4) and a concentration of HCO; "above physiological levels (i.e., above 29 ° mM In some embodiments, the pH of the composition can be between 4 and 7.7 and the concentration of HCO3 can be between 30 mM and 2 M). In other embodiments, the pH of the composition can be between 5.5 and 7, 4. In additional embodiments, the pH of the composition can be around 6.

[0072] Figure 5 shows a diagram of the amplitude and duration of an acid state change caused by different formulations of compositions of the present disclosure. The black, solid and dotted lines represent a major change in acid, that is, a composition with a high concentration of H + ions. However, the buffering capacity of the composition represented by the black dotted line is less than the solid line, so that the acid change is maintained for a shorter duration. The gray, solid and dotted lines represent less acid change, that is, a composition with a lower concentration of H + ions. Again, the ability to buffer between these compositions varies so that the acid change caused by the composition represented by the gray dotted line is maintained for a shorter period. The compositions of the present disclosure can be designed along these two spectra, amplitude of change and duration of change, according to the desired therapeutic properties and delivery schedules.

[0073] In other embodiments, the present disclosure provides a stable therapeutic composition, comprising a buffer solution comprising a pharmaceutical grade base and at least one pharmaceutical grade conjugated acid, characterized in that the buffer solution is sufficient to raise the physiological pH of an individual's bloodstream by 0.1 to 1.1, and characterized by the buffer solution having a buffering capacity sufficient to sustain raising the physiological pH of the bloodstream. In some embodiments, the buffering ability can be sustained for a period of time, for example 1 minute or 1 week. The compositions can additionally comprise vitamins, salts, acids, amino acids or salts thereof, and stabilized oxidizing species.

[0074] In another aspect, the compositions of the present disclosure may additionally comprise salts to provide sources of relevant physiological ionic species, such as Na ', K', Mgº !, Cl ”, POs *, or Ca. These may include, without limitation, sodium chloride, disodium phosphate, potassium chloride, monopotassium phosphate, magnesium chloride and calcium chloride. The compositions may additionally comprise other oligo elements and their salts, including, but not limited to: selenium, copper, chromium, iodine, fluoride, zinc, manganese, molybdenum and iron.

[0075] Sodium ions are required in relatively large concentrations for normal physiological functioning. It is the largest cation in the extracellular fluid. It plays an important role in many physiological processes including the regulation of blood volume, blood pressure, osmotic balance and pH, as well as the generation of nerve impulses.

[0076] Potassium ions are the main cations in intracellular fluid and with sodium ions in extracellular fluid, they are a primary generator of electrical potential across cell membranes. Consequently, they play a significant role in normal functioning and are fundamental in bodily functions such as neurotransmission, muscle contraction and cardiac function.

[0077] Calcium ions are equally important for many physiological processes. In particular, Ca ions? ” are the second most widespread messengers used in signal transduction. In endothelial cells, Ca ions? ” they can regulate various signaling pathways that cause relaxation of smooth muscles around blood vessels. Dysfunction in the pathways activated by Caº ** - can lead to an increase in tone caused by unregulated contraction of smooth muscle. This type of dysfunction can be seen in cardiovascular diseases, hypertension and diabetes.

[0078] magnesium ions are needed at relatively high concentrations in normal metabolism. Magnesium deficiency is recognized as rare, unless accompanied by severe losses in other electrolytes, such as vomiting and diarrhea. However, it is often recognized as deficient in the modern diet, with symptoms such as muscle tremors and weakness. This mineral is important in many enzymatic reactions and will stabilize excitable membranes. Administered intravenously, magnesium can produce an anesthetic action and this is indirect evidence of its action on the endothelial component of the vascular wall to stabilize and normalize the surface of the vascular wall.

[0079] In some embodiments, a composition of the present disclosure comprises Na 'at a concentration between 0.1 mM and 1 M. In other embodiments, a composition of the present disclosure comprises K * at a concentration between 0.0 mM and 1 M. In some embodiments, a composition of the present disclosure comprises Mg? * In a concentration between

0.1 mMel1lM. In other embodiments, a composition of the present disclosure comprises Ca? * At a concentration between 0.1 mMe1lM.

[0080] As described above, the interaction between the various ionic species is interrupted under various physiological conditions, and the compositions of the present disclosure may include these species to assist in the restoration of normal physiological conditions and concentrations. For example, high intracellular Ca? * Can be restored to a lower level as compensator for Mgº ', K', and H ', which can lead to the presentation of NOS in the cytosol and the restoration of NO levels.

[0081] As stated above, the compositions described in this document may include vitamins and vitamins, which is a substance (s) that has vitamin-like activity. The vitamins selected from the group, which consists of the water-soluble and lipid group, and a combination of two or more of these can also be added to the pharmaceutical composition. Preferably, the pharmaceutical composition includes ascorbic acid. Ascorbic acid is included as a strong antioxidant component and to maintain the structural integrity of connective tissue, including basal epithelial membranes and to promote wound healing. It can also play a distinct role as an agent with strong anti-inflammatory actions. It has been shown that the oxidized form of the vitamin, dehydroascorbic acid, transfers intracellularly where part of it is reduced within the cell by the action of glutathione. The deficiencies of other groups B and A and E are also protected by ascorbic acid and the corresponding interactions of dehydroascorbic acid and glutathione. In some embodiments, a composition of the present disclosure comprises dehydroascorbic acid, an oxidized form of ascorbic acid that is actively imported into the endoplasmic reticulum of cells via glucose transporters. The presentation of dehydroascorbic acid can also stimulate the production of glutathione in the liver, which facilitates recycling of dehydroascorbic acid in ascorbic acid. Thus, dehydroascorbic acid indirectly increases intracellular antioxidant resources. Dehydroascorbic acid can be present through the direct inclusion of pharmaceutical grade dehydroascorbic acid, or by converting ascorbic acid through contact with a reactive oxygen species, such as HOCl, H2O7 or OCl.

[0082] The B Vitamin Group has proven to be important in human food intake, and plays an important role, acting as coenzymes in cellular metabolism and energy production. The entire group of B vitamins can be included in the formulation to treat any deficiencies in the patient population to be treated.

[0083] The group of B vitamins are found naturally occurring together in foods and are generally included comprehensively for this reason. The B group includes: 1) Thiamine (Bl), which plays an important role in the production of energy within the cell, specifically as a coenzyme in carbohydrate metabolism. At least 24 enzymes are known to use thiamine as a coenzyme; 2) Riboflavin (B2) in the form of flavin mononucleotide and flavin adenine dinucleotide are part of all dehydrogenated enzymes.

Deficiency of this vitamin causes inflammation of the mouth, tongue, dermatitis, defective vision and blood dyscrasias; 3) Niacinamide (B3) is included, as part of the B group of vitamins as deficiency syndromes in the clinical pellagra are well-known clinical manifestations of deficiencies.

Deficiency states of this vitamin are associated with intestinal disease and alcohol misuse.

It also occurs in diabetes mellitus and carcinoid syndrome.

The active forms of this vitamin include the nicotinamide dinucleotides NAD and NADP, which are the coenzymes and cosubstrates of countless dehydrogenase responsible for oxidation reduction systems within the human cell, which are indispensable for energy production.

The formation of nicotinic acid from the nicotinamide administered in the formulation produces nicotinic acid which has additional actions not shared by nicotinamide, such as inhibition of cholesterol synthesis; 4) Calcium D-Pantothenate (B5), pantothenic acid forms a larger part of the coenzyme A molecule, which is important in the metabolic cycles that produce energy in the mitochondria of all cells.

The effect of this vitamin on several disease syndromes has been recognized.

Such as its use in the neurotoxicity produced by streptomycin and its use in diabetic neuropathy, skin diseases and adynamic ileum; and 5) Pyridoxine (B6) is widely used as a coenzyme and over 40 types of enzyme reactions.

The B group of vitamins can also help in providing an increase in antioxidants and stimulated glutathione to reduce reactive oxygen species, which ultimately helps in the expression of NO.

[0084] The most important are the transamination reactions and the influence of pyridoxine on tryptophan metabolism. Quinureninase, which is an enzyme used to identify pyridoxine deficiencies, loss of its activity when pyridoxine is not present and can result in secondary nicotinic acid deficiency as a result of the lack of kinureninase conversion from tryptophan nicotinic acid.

[0085] Cyanocobalamin (B1l2) is used due to frequent reports of cyanocobalamin malabsorption, caused by poor eating habits, senescence, and certain drugs (metformin) used as a hyperglycemic agent in diabetes mellitus. This vitamin is essential for normal erythropoiesis to occur, and recent discoveries have also implicated this vitamin in improving neuronal transmission in motor neuron diseases. (Rosenfeld, Jeffrey and Ellis, Amy, 2008, Nutrition and Dietary Supplements in Motor Neuron Disease, Phys Med Rehabil Clin N Am., 19 (3): 573-589).

[0086] Vitamin K is a fat-soluble vitamin. There are two naturally occurring forms of the vitamin. Vitamin K1 is Vitamin K in the diet and is abundant in green leafy vegetables, while vitamin K2 is present in tissues. Vitamin K2 is synthesized by bacteria. It is found mainly in fermented products such as fermented soy, cheese, curd and to some extent also in meat and meat products (Thijssen, H. H., M. UU.

Drittij-Reijnders, and M. A. Fischer, 1996, Phylloquinone and menaquinone-4 distribution in rats: synthesis rather than uptake determinations menaquinone-4 organ concentrations, JJ Nutr 126: 537-43). Vitamin K2 is found in animals like menaquinone. It is the activated human form of vitamin K and is said to promote healing of bone fractures. It is essential for the carboxylation of glutamate residues in many calcium-binding proteins, such as calbindin and osteocalcin. These proteins are involved in calcium uptake and bone mineralization.

[0087] There is an established daily dose for vitamin Kl, but not for vitamin K2. A typical oral therapeutic dose of vitamin K2 for osteoporosis is 45 mg / day. Unlike for coagulation, a much higher level of vitamin K is required for the full range carboxylation of osteocalcin (Booth, S. L., and J. W. Suttie, 1998, Dietary intake and adequacy of vitamin K, U. Nutr 128: 785-8). Vitamin K deficiency is associated with reduced hip bone mineral density and an increased risk of fractures in healthy elderly women. Animal studies have shown that the most potent form of vitamin K is vitamin K2, which was administered to mice at 0.1 mg / kg orally (Akiyama, Y., K. Hara, A. Matsumoto, S. Takahashi, and T. Tajima, 1995, Comparison of intestinal absorption of vitamin K2 (menaquinone) homologues and their effects on blood coagulation in rats with hypoprothrombinaemia, Biochem Pharmacol 49: 1801-7). Vitamin K2, in the form of menaquinone-4, is the most biologically active form. It has been extensively studied in the treatment of osteoporosis. In one of these studies, 241 osteoporotic women were given 45 mg / day of vitamin K2 and 150 mg of elemental calcium. After two years, vitamin K2 has been shown to maintain lumbar bone mineral density, significantly lower fracture incidence (10% versus 30% in the control group (Shiraki, M., Y. Shiraki, C. Aoki, and M. Miura, 2000 , Vitamin K2 (menatetrenone) effectively prevents fractures and sustains lumbar bone mineral density in osteoporosis, J Bone Miner Res 15: 515-21).

[0088] Vitamin K2, but not vitamin Kl, can inhibit arterial plaque calcification. In 1996, animal studies involving rats found that high doses of vitamin K2 (100 mg / kg body weight daily) inhibited the increase in calcium in the kidneys and aorta induced by megadose of synthetic vitamin D (Seyama, Y., M Horiuch, M. Hayashi, and Y. Kanke, 1996, Effect of vitamin K2 on experimental calcinosis induced by vitamin D2 in rat soft tissue, Int JJ Vitam Nutr Res 66: 36-8). A similar study was carried out with rabbits. High doses of Vitamin K2 (1-10 mg / kg daily for 10 weeks) inhibited the progression of atherosclerotic plaque in the aorta and pulmonary arteries (Kawashima, H., Y. Nakajima, Y. Matubara, J. Nakanowatari, T. Fukuta, S. Mizuno, S. Takahashi, T. Tajima, and T. Nakamura, 1997, Effects of vitamin K2 (menatetrenone) on atherosclerosis and blood coagulation in hypercholesterolemic rabbits, Jpn UT Pharmacol 75: 135-43).

[0089] Vitamin K2 was also observed to reduce levels of total cholesterol, lipid peroxidation, deposition of cholesterol ester in the aorta and the activity of factor X in plasma compared with the control group. A study involving more than 500 post-menopausal women investigated the relationship between vitamin K and vitamin K2 intake and coronary calcification. Sixty-two percent of the women sampled for the study had coronary calcification. Only vitamin K2 intake was associated with a tendency to decrease coronary calcification (Beulens, JW, ML Bots, F. Atsma, ML Bartelink, M. Prokop, JM Geleijnse, JC Witteman, DE Grobbee, and YT van der Schouw, 2009, High dietary menaquinone intake is associated with reduced coronary calcification, Atherosclerosis 203: 489-93).

[0090] In some embodiments, a composition of the present disclosure comprises one or more of the above vitamins or vitamins. A composition can comprise one or more of the above vitamins or vitamins in amounts between 1 µg and 1,000 mg per dose.

[0091] In some embodiments, a composition of the present disclosure may additionally comprise antioxidant compounds. These may include, but are not limited to: non-enzymatic compounds, such as tocofherol (aTCP), coenzyme Q10 (0), cytochrome c (C) and glutathione (GSH), and enzymatic components such as manganese superoxide dismutase (MnSOD) , catalase (Cat), glutathione peroxidase (GPX), phospholipid hydroperoxide qglutathione peroxidase (PGPX), glutathione reductase (GR); peroxiredoxins (PRX3 / 5), glutaredoxin (GRX2), thioredoxin (TRX2) and thioredoxin reductase (TRXR2). A composition can comprise one or more of the above antioxidant compounds in amounts between 1 µg and 1000 mg per dose.

[0092] In some embodiments, a composition of the present disclosure may additionally comprise a stabilized oxidizing species. The stabilized oxidizing species can be, without limitation, one or more of H2O, O2, H202, Cl170 and H30O.

[0093] Other adjuvants may include selenium and / or selenocysteine in concentrations of 60 to 90 µg per dose. Other adjuvants may also include other trace elements and their salts, including, but not limited to: copper, chromium, iodine, fluoride, zinc, manganese, molybdenum and iron.

[0094] In some embodiments, the compositions of the present disclosure can be formulated by combining pharmaceutical grade compounds in a stable therapeutic composition. The compounds can be added in desired amounts to a vessel, with water added to complete a final volume. In some embodiments, a composition of the present disclosure comprises a final volume between 5 ml and 500 ml. In other embodiments, a composition comprises a final volume of about 250 ml. In some embodiments, the composition can be supplied in 20 ml bottles. A composition of the present invention can be further diluted prior to administration. For example, a 20 ml bottle can be diluted with saline to a dispensed volume of 100 ml for administration. In other embodiments, the liquid formulation can be reduced to a dry solid via lyophilization. The lyophilized formulation can then be reconstituted to a specific volume before administration.

[0095] Table 1 shows various formulations of the composition, according to exemplary embodiments of the present disclosure per 20 ml bottle: Table 1 mg / mg / mg / mo / mg / mg / mg / mg / Component dose | dose [dose | dose [dose | dose [dose | dose L-ascorbic acid o 450 900 12 2,000 | 2,000 | O

USP Dehydric Acid 12,000 [2,000 | 4,000 ascorbic Thiamine 63.33 | 63.33 163.33 | 63.33 | 63.33 163.33 163.33 | 63.33 HCl USP Sulfate 808 sos 808 808 Magnesium

USP Cyan cobalamin | 1.93 [1.93 | 1.93 [1.93 | 1.93 | 1.93 1.93 | 1.93

USP Niacinamide | ,, 7 Usp 119 119 119 119 119 119 119 119 Pyridoxine | 119 119 119 119 119 119 119 119 HCl USP 7 7 Riboflavin S "Phosphate [2.53 | 2.53 [2.53 [2.53 | 2.53 [2.53 2.53 | 2.53

USP Calcium D- Pantothenate | 2.93 2.93 2.93 2.93 2.93 2.93 2.93 2.93 2.93

USP Sodium Bicarbonate 840 840 840 840 3.36 3.36 | 3.36

USP WFI (water for balancing Jequil. | Balancing balancing balancing balancing / balancing injection)

dose dose dose dose dose dose dose dose n o la ds de lo da bo bo | with WFI (mM & 20ml) 250 125 6.5 6.5 250

[0096] In some embodiments, the components of the compositions in Table 1 may vary from the values listed by plus or minus 1%, 2%, 5%, or 10% according to the therapeutic need. The compositions in Table 1 can also additionally comprise components as described above, according to the therapeutic need.

[0097] In some embodiments, the compositions of the present disclosure can be stabilized to improve service life. The compositions can be stabilized by suitable techniques known to those skilled in the art, including, but not limited to: freezing, freeze-drying, use of UV bottles or spectral blocking (for example, amber bottles), overflowing with stabilizing gases such as nitrogen, bubbling a stabilizing gas through the solution, separating reactive species in multiple vials to be combined for use, and stored in a cold chain. As a non-limiting example, the acid and buffer components of a composition can be separated into two bottles. Other components of the compositions of the present disclosure (for example, cyanocobalamin, calcium d-pantothenate and / or others) can be included in these vials or further separated into additional vials.

Treatment Methods

[0098] In another aspect, the present disclosure provides treatment methods. The methods of the invention involve administering the composition of the invention to individuals in need thereof.

[0099] One embodiment of the invention is a method of treating or ameliorating a mitochondrial disorder, metabolic disorder, a condition associated with diabetes, cardiovascular dysfunction, or an eye condition in an individual in need of it, by administering to the individual a composition stable therapy of the present disclosure.

[00100] Mitochondrial dysfunction, characterized by a loss of efficiency in the electron transport chain and reductions in the synthesis of high energy molecules, such as ATP, is a characteristic of aging and essentially, of all chronic diseases. As used herein, the term "mitochondrial disorder" refers to a condition or disorder characterized by mitochondrial disorder, and includes, for example, neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis , and Friedreich's ataxia, cardiovascular diseases, such as atherosclerosis and other cardiac and vascular conditions, diabetes and metabolic syndrome, autoimmune diseases, such as multiple sclerosis, systemic lupus erythematosus, and type 1 diabetes, neurobehavioral and psychiatric diseases, such as disorders of the autism spectrum, schizophrenia and bipolar disorders and mood disorders, gastrointestinal disorders, stressful diseases, such as chronic fatigue syndrome and Gulf War diseases, musculoskeletal diseases such as fibromyalgia and skeletal muscle hypertrophy / atrophy and chronic infections.

[00101] As used in this document, a "metabolic disorder" refers to diabetes, insulin resistance, glucose intolerance, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia or hyperlipoproteinemia. the terms “diabetes” and “diabetes mellitus” are understood to encompass both insulin-dependent and non-insulin-dependent diabetes mellitus (Type 1 and Type 2, respectively), “gestational diabetes, as well as pre diabetes, unless a condition or another is specifically indicated.

[00102] As used in this document, a "condition associated with diabetes" includes obesity, hypertension, hyperlipidemia, fatty liver disease, nephropathy, neuropathy, kidney failure, retinopathy, diabetic ulcer, cataract, insulin resistance syndrome and cachexia.

[00103] As used herein, "cardiovascular dysfunction" includes conditions and diseases, such as coronary heart disease, cerebrovascular disease, hypertension, peripheral artery disease, occlusive arterial disease, angina, rheumatic heart disease, congenital heart disease, heart disease , heart failure, palpitations, supraventricular tachycardia, fibrillation, fainting, dizziness, fatigue, migraine, high levels of total blood cholesterol and / or LDL cholesterol, low level of HDL cholesterol, high level of lipoprotein, heart infections, such as carditis and endocarditis, diabetic ulcer, thrombophlebitis, Raynaud's disease, anorexia nervosa, lameness and gangrene, atherosclerosis and peripheral artery disease. Diseases and conditions that are especially suitable for treatment or amelioration with a pharmaceutical grade buffer composition as described herein are peripheral artery diseases and atherosclerosis.

[00104] As used in this document, the term "eye condition" refers to pathological conditions pertaining to the eye, and may include, but is not limited to: glaucoma, macular degeneration, light sensitivity problems, calcium-based floats and collagen, correction of lens stiffness.

[00105] Another embodiment of the invention is a method of treating or ameliorating a dermatological condition by administering to the individual a stable therapeutic composition of the present disclosure; as used herein, the term “dermatological condition” refers to skin-related disorders, conditions and diseases, such as skin aging, wrinkles (including, for example, expression lines and wrinkles around the eye), acne, damage per photo, rosacea, scars, eczema, alopecia, hypertrophic scars, keloids, stretch marks or Striae distensae, psoriasis, pruritus, Ehlers-danlos syndrome, scleroderma, post-inflammatory hyperpigmentation, melasma, alopecia, civatte poikiloderma, vitiligo, discilio skin, burns and blotchy pigmentation.

[00106] In another aspect, the present disclosure provides a method of modifying an individual's metabolism, the method comprising administering to the individual a stable therapeutic composition, comprising a buffer solution comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffering agent, characterized in that the buffer solution is sufficient to reduce the physiological pH of an individual's blood stream by 0.01 to 1.1, and characterized in that the buffer solution has a buffering capacity sufficient to sustain the reduction of the physiological pH of the individual's bloodstream for between 1 minute and 1 week.

[00107] A different embodiment of the invention provides a method of reducing the lactate load in an individual in need thereof, by administering to the individual the composition of the invention. The reduction of lactate load has been described extensively above in this document.

[00108] In another embodiment of the invention, the present disclosure provides a method of reducing acidosis in an individual in need of it, by administering to the individual the composition of the invention. Acidosis reduction has been described extensively above in this document.

[00109] In another embodiment, the present disclosure provides a method of treating a disorder of the central nervous system in an individual in need thereof, by administering the composition of the invention. As used in this document, the term "central nervous system disorder" means any neurological disorder that affects the structure or function of the brain or spinal cord.

[00110] In another embodiment, the present disclosure provides a method of treating chronic injuries to an individual, by administering the composition of the invention. In some embodiments, the present disclosure provides a method for inducing accelerated wound healing in an individual, the method of administering a stable therapeutic composition of the present disclosure.

[00111] In another embodiment, the present disclosure provides a method that improves an individual's mental or physical performance by administering the composition of the invention.

[00112] Routes of administration for a therapeutically effective amount of the composition of the present disclosure include, but are not limited to: intravenous, intramuscular, or parenteral administration, oral administration, optical administration, topical administration, administration by inhalation or other nebulization , transmucosal and transdermal administration. The compositions of the present disclosure can also be formulated for intravenous, bolus, dermal, oral, optical, suppository, buccal, ocular or inhalation administration. For intravenous or parenteral administration, that is, injection or infusion, the composition may also contain suitable pharmaceutical diluents and carriers, such as water, saline, dextrose solutions, fructose solutions, ethanol or oils of animal, vegetative or synthetic origin . It may also contain condoms and tampons as they are known in the art. When a therapeutically effective amount is administered by intravenous, cutaneous or subcutaneous injection, the solution may also contain components to adjust the pH,

tonicity, stability, and the like, all of which are within the knowledge of the matter. For topical administration, the composition can be formulated into, for example, liquid, gel, paste or cream. In some embodiments, the composition can be administered via a topical adhesive. For ocular administration, the composition can be formulated in, for example, liquid eye drops, or as a gel, paste, or cream to be applied to the surface of the eye and / or the surrounding tissue. For optical administration, the composition can be formulated into, for example, ear drops.

[00113] A composition for intravenous, cutaneous, or subcutaneous injection should contain, in addition to the peptide, an isotonic vehicle, such as Sodium Chloride Injection, Ringer Injection, Dextrose Injection, Dextrose Injection and Sodium Chloride, Buffer Citrate for Injection of Ringer with lactate pH 5.5, or other carriers, diluents and additives as known in the art. As - described completely elsewhere in this document, the pharmaceutical composition of the present invention may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those skilled in the art. The pharmaceutical compositions are formulated for intravenous or parenteral administration. Typically, compositions for intravenous or parenteral administration comprise a suitable sterile solvent, which can be an isotonic aqueous buffer or a pharmaceutically acceptable organic solvent.

[00114] As fully described elsewhere in this document, where necessary, the compositions may also include a solubilizing agent. Compositions for intravenous or parenteral administration may optionally include a local anesthetic to decrease pain at the injection site. Generally, the ingredients are supplied separately or together and mixed in unit dosage form in an airtight container, such as an ampoule or sachet. Pharmaceutical compositions for administration by injection or infusion can be dispensed, for example, with an infusion bottle, containing, for example, water or sterile pharmaceutical grade saline. Where pharmaceutical compositions are administered by injection, an ampoule of sterile water for injection, saline, or other solvent, such as a pharmaceutically acceptable organic solvent, can be provided so that the ingredients can be mixed before administration.

[00115] The duration of intravenous therapy, using the pharmaceutical composition of the present invention, will vary, depending on the condition, being treated or improved and the condition and potential idiosyncratic response of each individual mammal. The duration of each infusion is <1 minute (for example, bolus injection) to about 1 hour (intravenous administration). The infusion can be repeated within 24 hours. Thus, a mammal can receive about 1 to about 25 infusions per day. Preferably, the number of infusions per day is 1 or 2. The period between each infusion can be 1, 2, 5, 10, 20, 30, 40, 50 minutes, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours or more. The administration can also be administered in any variety of cadence, including hourly, daily, weekly, monthly, quarterly, biannual, annually, etc., or any other specific period, depending on the condition to be treated and / or the response of each individual mammal. In other embodiments, a pharmaceutical composition of the present invention can be administered as a single event, or can be administered over durations of one week, several weeks, months, years, or several years, or for any other desired duration, as needed.

[00116] Alternatively, the infusions can be administered one after the other without a substantial period in between. In one embodiment, the infusion lasts for about 45 minutes. The dose can be repeated 2-3 times in a week, depending on the severity of the relative or absolute nutrient deficits in the patient. A clinical evaluation may be necessary in order to establish the condition, but it may be limited to a review of medical history, subjective review of symptoms, subjective opinion of the mammal when human or after review of which specific deficits.

[00117] In another administration embodiment, the administration is alternated between two solutions: an acid change (AS - Acid Shifting) and a change of base (BS - Base Shifting) as described above. Alternate administration of AS / BS / AS / BS at various rates can be expected to induce further pH changes from acid to base or from base to acid. Such events, as induced by exercise, are recognized for their value in promoting the release of nitric oxide (NO - Nitric Oxide) for vasodilation (Capellini, Verena K., et al., 2013, Nitric Oxide Concentration in Endothelial and Smooth Muscle Cells from Rat Aorta, PLOS One, 8 (5): e62887), and to promote cardiolipin repair and remodeling (Khalafat, Nada, et al., 2011, Lipid Packing Variations Induced by pH in Cardiolipin-Containing bilayers: The Driving Force for the Cristae-Like Shape Instability, Biochimica et Biophysica Acta - Biomembranes, 1808 (11): 2724- 2733). These altered administrations can last between 0.5 and 60 minutes, and can be alternated once, twice or more as needed to achieve the desired therapeutic effect. The AS and BS administrations do not necessarily have to be identical in the effect of change or duration of administration. That is, for example, an AS composition can affect a major change over a short administration, while the BS composition can affect a minor change over a longer administration. In some embodiments, an exemplary administration profile can be a 5 minute AS administration followed by a 10 minute BS administration, repeated twice (i.e., 5/10/5/10). Other exemplary administration profiles can be, for example, 10/10/10/10 or 0.5 / 0.5 / 0.5 / 0.5.

[00118] Systemic formulations include those designed for administration by injection, for example, subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection. Useful injectable preparations include sterile suspensions, solutions or emulsions of the active compound (s) in an aqueous or oily vehicle. The compositions can also contain solubilizing agents, formulation agents,

such as suspending, stabilizing and / or dispersing agents. Injection formulations may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, and may contain additional preservatives. For prophylactic administration, the compound can be administered to a patient at risk of developing one of the conditions or diseases previously described. Alternatively, prophylactic administration can be applied to prevent the appearance of symptoms in a patient who is suffering or formally diagnosed with the underlying condition.

[00119] The amount of compound administered will depend on several factors, including, for example, the particular indication being treated, the mode of administration, whether the benefit is prophylactic or therapeutic, the severity of the indication being treated and the age and weight of the patient, the bioavailability of the particular active compound and the like. The determination of an effective dosage is within the capabilities of those skilled in the art coupled with the general and specific examples disclosed in this document.

[00120] The formulations can comprise other ingredients for the treatment of the organism as a whole. For example, an antioxidant additive and / or pro oxidant additive may be present. The latter may be an agent that acts as a preventative, while the former may be an agent that acts to treat a specific medical condition.

[00121] Treatment effectiveness can be determined by measuring biomarkers before, during and / or after administration of a composition of the present disclosure, or before, during and / or after administration of a course of treatment, using the compositions of the present disclosure .

Exemplary biomarkers, and the indications for which they can be used, are shown in Table 2, and may include, for example, AlMicro, tubular disorders and electrolyte imbalance; A2Macro, small vessel brain disease, liver fibrosis; ACE, high blood pressure, heart failure, diabetic nephropathy; Adiponectin, vascular disease, metabolic syndromes; Apo A-I, high density lipid particles; Apo A-II, HDL metabolism; Apo C-II, ischemic stroke, heart disease; Apo C-III, metabolic syndrome and hypertriglyceridemia; Apo H, type 2 diabetes, metabolic syndrome; AT-III, venous thrombosis, abnormal coagulation; B2M, peripheral arterial disease; BDNF, psychiatric disorders; CD163, HIV infection, inflammation, cardiovascular disease; CD40, atherosclerotic instability; CD40-L, cell proliferation; CgA, tumors; Peptide C, metabolic syndrome; CRP, inflammation and tissue damage; Cystatin-C, cardiovascular disease, electrolyte imbalance; EGF, cell proliferation; EN-RAGE, inflammation, heart disease; EPO, anemia, chronic kidney disease; E- Seletin, inflammation, electrolyte imbalance; Factor VII, thrombosis (blood clotting); Ficolin-3, diabetic peripheral neuropathy; FRTN, blood disorders, anemia; FSH, pregnancy complications; GDF-15, mitochondrial diseases; Total GLP-l1, Type 2 diabetes, insulin secretion; HB-EGF, epithelial cell proliferation (inflammation); ICAM-1, inflammation; IFN-gamma, inflammation and immune response; IL-1 alpha, inflammation; IL-1 beta,

inflammation; IL-10, inflammation; IL-12p40, inflammation, multiple sclerosis, Alzheimer's disease; IL-12p70, peritonitis, inflammation; IL-15, Alzheimer's disease; IL-17, inflammation, lupus, cerebral vasculitis; IL-18, metabolic syndrome, acute kidney injury; IL-lra, inflammation; IL-2, inflammation; 1IL-23, inflammation, lupus; I1IL-3, inflammation, cell growth, proliferation and differentiation; IL-4, inflammation; IL-5, inflammatory factors, asthma, chronic obstructive pulmonary disease; IL-6, inflammation; IL-6r, coronary heart disease; IL-7, chronic obstructive pulmonary disease; IL-8, inflammation; IP-10, complications related to tuberculosis; LH, infertility; Lp (a), cardiovascular diseases; MCP-l1, inflammation; MCP-2, tuberculosis; MCP-4, asthma, metastasis; M-CSF, metabolic, hematological and immunological abnormalities; MIG, heart failure and left ventricular dysfunction; MIP-1 alpha, expression of cytokines for high-fat diet, wound healing; MIP-1 beta, autoimmune disorders; MIP-3 alpha, tissue damage in ischemic stroke and autoimmune diseases; MMP-3, ischemic and hemorrhagic stroke; MMP-9, ischemic and hemorrhagic stroke; MPIF-1, Kawasaki disease (inflammation in the walls of some blood vessels); MPO, inflammation and ischemia; Myoglobin, inflammation and ischemia; NAP-2, hepatitis B; NGF-betac, Alzheimer's disease, Alzheimer's; Nr-CAM, Alzheimer's disease, cognitive disorders; Osteocalcin, osteoporosis, Bone formation ;; PAI-1, metabolic syndrome; PARC, Gaucher disease (enlarged liver / spleen); PDGF-BB, development of osteoblasts and bone formation, liver fibrosis; PEDF, cardiometabolic disorders; Periostin, asthma; PLGF, angiogenesis, vasculogenesis and lymphangiogenesis; PPP, endocrine pancreatic tumors; PRL; P-Seletina, inflammation; RAGE, chronic inflammatory diseases; RANTES, abdominal aortic aneurysm, viral diseases; Resistin, inflammation, cardiovascular disease; S100-B, brain damage and interruption of the blood-brain barrier; SAA, inflammation; SAP, chronic and acute inflammation; SCF, tumor proliferation; SHBG, thyroid disorders, pituitary diseases; SOD-1, brain damage and interruption of the blood-brain barrier; TAFI, arterial thrombosis, acute ischemia; TBG, thyroid-related disorders; TIMP-l1, tissue remodeling, thyroid-related disorders; TN-C, myocarditis; TNF-alpha, inflammation; TNF-beta, inflammation, cardiovascular disease; TNFR2, ischemic stroke, insulin disorders; TTR, metabolic and septic disorders; VCAM-l1, inflammation; VEGF, angiogenesis, hypoxia; Vitronectin, Alzheimer's disease; and vWF, arrhythmia, acute arterial damage. Table 2 Biomarkers | Regulation Range Relevance Level II Reference during Pathological Disease Status E-Seletina 30 pg / ml - | Up Inflammation - EEE L-Seletina 100 pg / ml - | Above Inflammation

FF EFE

Biomarkers | Interval | Regulation Level II Relevance Reference during Pathological Disease Status P-Seletina 20 pg / ml - 30 | Above Inflammation

FESP Adhesion 150 pg / ml - | Above Intercellular Inflammation / 20 ng / ml Molecule-l (ICAM-1) Molecule of 0.3 ng / ml - | Above Inflammation Adhesion 60 ng / ml Vascular cells-1l (VCAM-1) Factor of 1 pa / ml - 200 | Above Proliferation Growth pg / ml Epidermal Cell (EGF) Interferon-g 15.6 - 1,000 | Above Response (IFN-g) pPg / mL Inflammation and Immune Interleukin- | 0.5 pg / ml - | Above Inflammation

EEE Interleukin- [0.3 pg / ml - | Above Inflammation Eme Interleukin- | 4 Pg / ml - | Above Inflammation Es

Biomarkers | Interval | Regulation Relevance of Level II Reference during the Pathological State of the Interleukin- Disease | 5 pg / ml - 200 | Above Inflammation on Interleukin- 3 pg / ml - | Above ESTO 1 Interleukin- Inflammation | 1 pg / ml - 600 | Above EE Inflammation = Interleukin- | 1 pg / ml - 150 | Above Inflammation Fes qe Protein 2 pg / ml - 500 | Above Chemotactic Inflammation pg / ml Monocytes-1 (MCP-1) Factor 30 pg / ml - | Up Inflammation Necrosis 6,000 pg / ml Tumoral-a (TNF-a) Factor | 31-86 pa / mL Above Hypoxia Vascular Endothelial Growth (VEGF) SAA 0.5 ng / ml - | Above Inflammation PE q and Fibrinogen 150-400 Above Thrombosis

WHAT IF

Biomarkers | Interval | Regulation Level II Relevance Reference during Pathological Disease Status C-Protein 0-10mg / dl Above Inflammation and Reactive (CRP) Tissue Damage

Apo Al Macho: 94-176 | Above High mg / dL; Density of

Female: 101- Particles

198 mg / dl of Lipidio Apo B Male: 52-109 | Above Low mg / dl; Density of

Female: 49-103 mg / dl particles of Lipid Insulin 4 pIU / ml - Above Proinsulin Syndrome 0.313 ng / ml Above FE En E C-peptide Syndrome 0.156 ng / ml Above E Myeloperoxide Syndrome | Adult Above Inflammation and if Male = $ 50 Meg / 1 ischemia; Female

Adult = 930 meg / 1 CD40 Calling 32-2,000 Above Proliferation FE nr Es

Biomarkers | Regulation Interval Relevance Level II Reference during the Pathological State of the Disease Panel | Altera Altera Disease Cardiovascu- biliary acids (16 home bile acids) Kit p180 (188 Altera Altera Risk Cardio "endogenous metabolic metabolites of compound classes) Oxidized LDL 30- Above Stress

2,000pg / ml Oxidative and Low Density Lipid Particle sT2 0.156-- Above Inflammation and Brain 0-5.0 na / ml Above Muscle Inflammation of Creatine Kinase (CK-MB)

Biomarkers | Interval | Regulation Level II Relevance Reference during the Pathological State of the Disease

Protein from | 102-25,000 Above Inflammation and Connection to | pg / ml Thrombosis Heart Fatty Acids (H-FABP) Myoglobin Male Above Inflammation and (Myo) Adult = <$ 50 Ischemia meg / 1; Female

Adult = <30 meg / 1 Troponin 1 / <0.05 ng / ml Above Disease (cTnI) Cardiovascu-

home

Adiponectin 0.38-12 Above Inflammation and ng / m (www. K- Assay.com disease) Heart Cystatin C 0.3 ng / ml - | Up ng / ml Cardio vascular disease

Catalase 0.313 ng / ml | Above Stress Fe F E p53 3.1 U / ml —- | Below Apoptosis Do se TO |

KIts

[00122] One embodiment of the invention includes a kit for administering the stable therapeutic composition of the present disclosure to an individual. In this embodiment, the kit can contain the composition in a single bottle or in more than one bottle. The vial may preferably be an injection vial with a membrane that is suitable for inserting a syringe to draw the solution out of the vial or a soft I.V. The composition of the invention is contained in the bottle in a sterile aqueous solution. The solution can be supplied as a concentrated solution, to which a diluent is added before administration. The diluent can be sterile water. The kit may additionally comprise a pre-filled container containing the diluent. In a preferred embodiment, the soft infusion bag is pre-filled with diluent. Alternatively, the composition vial may contain a solution that is in a concentration that is suitable for injection without any dilution. Preferably, the solution for injection is isotonic. That is, the solution may contain salt, carbohydrates, such as glucose, NaHCO3 or amino acids, such as glycine, and is isotonic with blood plasma. In other cases, the solution may be hypotonic, in order to promote faster intracellular uptake or hypertonic, in order to promote slower intracellular uptake.

[00123] In one embodiment of the invention, the kit contains two bottles. The first vial contains at least one pharmaceutical grade acid in a sterile aqueous solution. For example, the first bottle may contain pharmaceutical grade ascorbic acid, thiamine HCl, magnesium sulfate, cyanocobalamin, niacinamide, pyroxidine HCl, riboflavin 5 'phosphate, calcium D-pantothenate and an aqueous solvent, containing sodium chloride and water (for injection ). The second vial contains at least one pharmaceutical grade pH buffering agent in a sterile aqueous solution. For example, the second vial may contain pharmaceutical grade sodium bicarbonate and an aqueous solvent, containing sodium chloride and water (for injection). The contents of the vials can be stored under refrigeration or under freezing conditions.

[00124] In another embodiment, the kit may contain a container of a lyophilized powder that can be reconstituted prior to administration. The lyophilized powder can be an isotonic solution.

[00125] Each kit described in this document may additionally comprise instructions for use. The instructions will, of course, depend on the kit itself and whether a diluent should be used or other components to be mixed with the pharmaceutical grade buffer solution prior to administration.

EXAMPLES Example 1

[00126] The experiments described in this document were designed to validate key aspects of the use of acidic buffered solutions to alter the acidity of the bloodstream pH for therapeutic purposes. Specifically, several aspects are illustrated: (1) blood has acid-base properties that can be considered in general as a solution having a physiological pH and buffering capacity. In addition, therapeutic compositions designed to change the pH of the blood after administration can generally be considered as solutions having a target pH and the ability to buffer. (2) the change in the pH of the bloodstream towards acidic conditions can be achieved via intravenous or intraarterial administration of an acidic solution. (3) Alternative formulations, having higher concentrations of buffer components, increase the ability to prevent the restoration of the pH of the blood stream back to physiological. (4) The faster dissolution of calcified mineral forms can be achieved when conditions are changed from equilibrium at a given pH to lower pH levels.

[00127] The logic, protocol and results of these experiments are described in the following sections. Blood acid-base properties

[00128] Under normal physiological conditions, it is recognized that the blood generally has a pH value close to 7.41. This is due to the presence of various acids within it (mainly HCl) and various buffers (mainly bicarbonate). In the interest of developing a substitute to emulate the acid-base properties of the blood, a water-based solution containing HCl and HCO was prepared. HCl and HCO; the main species of acids and buffers in the blood were chosen for this substitute. For this blood substitute, 0.0024 M HCl in 5,000 ml of aqueous solution was buffered with 0.025 M NaHCO3z, to produce a resulting pH of 7.41 (Table 3). This substitute was freshly prepared for each of the tests that were performed,

as the loss of CO will influence the pH over time if left to atmospheric exposure.

[00129] Similarly, drug products designed to alter the pH of the blood can be formulated using a variety of physiologically compatible acids and buffers. To illustrate this, 4 examples of drug products were formulated (C1l-C4: Table 3), using HCl and NaHCO; as examples of acid and buffer components (Blood and Drug Compositions, according to Table 3, below). For the project, they would have pH below the physiological and would also be composed of buffer products. Cl was designed to provide a small pH change for a short period of time, C2 was designed to provide a small pH change for a long period of time, C3 was designed to provide a large pH change for a period of time short time, and C4 is designed to provide a large change in pH over a long period of time.

what? R 3 8 is +15 to 8 18 there 18 from 4: 8 18 ds 8 & & || & e [He 8 5 | 8 AND 5 AND 8 8

8. io e 8 [E E 8 Bo | 8 fe Es 3 8 E and E Es lg 18 5 a% 3 | é | 8 | as lg | | S o a and H o a js bs. dE | 8 | "dE pj | | º e E FM ig ig a É Ã d É da ds 3 de des 3 EE BB Ss% & || $ &: | s | ss FEM CA e | s 3 is de ls <is ls ss E ection

EM FP q a R E i EE EE z ã R PE) o = | s = s s = | s E DEF 1 DEF 34 ce e | E: FF

It's FR = Link. a Fi á and Pi SAN E ANN = e | a is it from la lb? ts 2 le do 33 | a = 3 E ss |] 7 «Ez iz; ig ig Ss be 38

EE EE q 4 FR o o o | a o g - o | to 4. 8 || Bs 2. 8 || 3 Es jo [8 | ê is je || a v Ss s | s o s 8 o if Ha ii. ii. 8 88 88 EE 88 $ is 4 a

F H 4 8 a | 8 8 ã | 4 3 8 3 4 8 FE gi 8 8 | 8 gi 8 | ace and e | á is e | “2 + le E] 8 at + FB a 2 2 8 faith | ag 2 8 7 It's healthy 8 8 there 18 | It's 8 | & 8 is 3 is & is | 8 | [8 | é é à à ler e fê + Es E E Eis ss sane 15 E Is ls E à ds | à | 3 é là | 3 8 | 3 | is |

Ss ã Ss "EZE 3 e 8 le 18 a se é la 8 la o = P Ss 4 Ss oa Ss H = s S. & & 6 é | s Ss. & = Ls e | S & 38 | 8 8 | S & 8 [is 8 88 8 ã [88132 & | 5 88 is 4 | FM & | FE s 4 8 as | ns oovo come oovo <ao & o “o <ao ma oo?? 8 8 ds EE)" => la la xa 58 | : R and SE || And E ak Ss ZE les s ja e Ns

EE Fr Oz õ & 4: oo à i aê 3 T & "o & mn ooa of ds - x 8 ss e [Ss o? Ss 8 ss Ss â ER Re s Ef effects> FS o Ss o S 3 | s | s S â 80 E q 6 E 8 & 8 | o no o Fo = no ooo Ro A 8 3 le le s à bjs E "e é E 8 4 Ss = S à NNE and ETs s | nv Tee = fl Ss 8 e e 2 and EE e 4 4 l and 2 ER ONE and ER; 3 healthy ls = es 1/18 is 5 2 is it? o Z ds 3 s

S SEL le le o E E PA 2 le fe 8 ls | 8 4 Ss 8 e E e E <Bo ss R Ss “o“ o x 3 O 3 O

2. Ox Ox F | o o Ê 8 8 “B 4 to S 25 la la la a 23 le a lo A | E dB lg 8 s ES and RB Ss F 3 | 8 | 8S Ss ez E EB E E == je | B B E B SB E: ã BB: ã BR: 2 to le ls | = is li ks s 8 88 8 8 88 88 8 8 & 8 & - o o o | o o o o 5- lo ss Ss 4- lo 8 Ss HH 8 ae ER is ix k e E: x OE o o o oE o o 4> -> = Ã 4 z a º z a É 4 4 g 4 4 8 Ê o É: é 4 | o o PF) 8 gã gã 8 [18 | 5 g g 8 8 Es E 4 8 | Sã es E ês Es n 3 there | 8 8 = E fa | 4 ã e ER ã 3 8 E o o 2 k o FNE ”o 8 g and + [8181 28 o 8 + E 2 8 & 1 | as 8 & | º R ions 85 8 8 [8/8 | Es ds 8 | [188 É à és [8 [exe | É é ja [é lots 2 E Ss 83 8s8 | 88 ES 8 3 [882 À ns ss [5 5 SS | ss = [is 5 (585 ê 8 8a 8 | ER | E 3: already | 88

[00130] First, Cl, C2, C3, and C4 were formulated, as well as blood substitutes, and the pH was measured. The pH was also calculated using the Henderson-Hasselbalch equation. Second, the compositions Cl, C2, C3, and C4 were added to the substitute blood. Again, a pH value was calculated, and a pH value was measured. After administration to the blood stream, each of the therapeutic solutions in the example changes the pH of the blood stream from physiological standard conditions (eg, pH 7.41) to reduced pH (eg, pH 7.31 - 6.70) . This is demonstrated by adding Cl (or 2, 3, 4) to the blood substitute solution, as summarized in Table 3. In this case, therapeutic formulations with the lowest pH and / or the highest buffer fraction are capable of conferring a major change in bloodstream pH.

[00131] To demonstrate the resilience of the therapeutically displaced blood to resist physiological return, a fixed amount of bicarbonate was added to each of the therapeutically displaced blood solutions. This was done to simulate pH restoration effects, such as stimulation of additional buffer sources, CO breathing; and renal action to remove H * and recycle HCO3z. Such restorative forces were stimulated by administering a fixed allocation of HCO3 "to the therapeutically displaced blood substitute solution. For a given amount of added bicarbonate, the different resilience of the C1-C4 compositions to resist the restoration of blood pH can be As shown in Table 3, resilience to restoration can be expressed in terms of pH delta / HCO; gram where a lower value implies a greater ability to resist the forces of pH restoration. In this example, formulations with more capacity buffering (C2 or C4) are more resistant to restoring to physiological per gram of bicarbonate added to restored pH.

[00132] To demonstrate the ability of calcium salts to dissolve more quickly in lower pH solutions, such as would be the case of calcified plaques in a bloodstream with a pH change, the calcium salts were submerged in a blood substitute solution with therapeutic pH change and dry weight after the selected time of submersion.

[00133] For this purpose the blood substitute was first exposed to a large amount of calcium salt for an extended period, while at pH 7.41 to establish the salt balance at the initial pH. Then, the residual solid calcium salts were removed, leaving a blood substitute solution that was almost saturated with the calcium salt at pH 7.41. Then, the Cl (or 2, 3, 4) formulations were added to the calcium saturated blood substitute to reduce the pH. Then the 2g tablets of the calcium salts were submerged in solution therapeutically altered to pH and weighed dry at selected intervals to establish a rate of weight loss (Table 4). As the surface area and shape of the calcium mineral were common for all tests, the test demonstrates that lower pH solutions promote higher dissolution rates than higher pH solutions

(approximately 0.043-0.0449 / min for pH 7.31 versus 0.054-0.059g / min for pH = 6.7)). Table 4.. Ca2 + weight (9) Dissolution Rate (g / min) minutes E to j | still, [02 me to [rem ee preceneess ie. Ca2 + weight (g) Dissolution Rate (g / min) minutes at | belts [one o fr se weighs, Ca2 + weight (9) Dissolution Rate (g / min) minutes pints [02 me to [rem e e presence, Ca2 + weight (9) Dissolution Rate (g / min) minutes

[00134] It will be evident to a person skilled in the art that various combinations and / or modifications and variations can be made in the compositions of the present disclosure, depending and as dictated by the therapeutic needs of the patient. In addition, features illustrated or described as part of one embodiment can be used in another embodiment to produce an embodiment even more further. Example 2

[00135] Studies were conducted, administering the therapeutic composition to three horses. The following materials were prepared for the study:

1. Subject 1 - mare, 34 years old, Welsh Cross, 739 pounds, with a history of pre diabetes, Laminitis with Cushing's disease and presentation of Lymes.

2. Subject 2 - gelding (eunuch), 13, Welsh Cross, 724 pounds, history of Laminitis with Cushing's disease and presentation of Lymes.

3. Subject 3 - mare, 12 years old, Welsh Cross, 652 pounds, Lymes performance history. 4, Each Treatment involves the administration of an intravenous buffer solution: a. 100 ml solution of AS * Bottle A (containing ascorbic acid, hydrochloric acid and aqueous solvent, containing sodium chloride and water), or 100 ml solution of ASVM ** Bottle A (containing ascorbic acid, dehydroascorbic acid, hydrochloric acid, thiamine HCl, magnesium sulfate, crystalline cyanocobalamin, niacinamide, pyroxidine HCl, riboflavin 5 "phosphate, and calcium D-pantothenate and aqueous solvent, containing sodium chloride and water).

B. Bicarbonate solution 100 ml Bottle B (containing sodium bicarbonate and an aqueous solvent, containing sodium chloride and water). ç. 1000 ml saline solution and a ready IV bag, or 2000 ml saline solution in a ready IV bag. * AS - Acid source grade composition ** ASVM - Acid source grade composition, additionally containing selected Vitamins and Minerals. Methods: Doses of the therapeutic composition were managed as follows: Table 5. Dosage of Subject 1 DOSE 1 DOSE 2 DOSE 3 | DOSE 4 | DOSE 5 TE] 100 ml bottle Be | Bottle A 100 ml x x x x x Er TA Bottle B x x x x “x Bicarbonate 100 ml Saline Solution x x x x x Er AA Saline Solution

FETUS

Table 6. Subject 2 Dosage DOSE 1 | DOSE 2 | DOSE 3 | DOSE 4 | DOSE 5

EEE EE Flask A 100 x Fr Flask A 100 ml x xXx x x Fr AOS Flask B 100 ml xXx xXx x x x

ET Saline Solution x x x x

FT AE Saline Solution x

FT O Table 7. Subject 3 Dosage DOSE 1 | DOSE 2 | DOSE 3 | DOSE 4 DOSE 5

EEEETE Bottle 100 ml x

FT LI Bottle A 100 ml x x x x Fr AO Bottle B 100 ml x x x x x

EA Saline Solution x x x x x

FO Fo Saline Solution

[00136] The dosage was administered as follows:

The products in bottle A were refrigerated at 40ºF before use, while the products in bottle B were stored at 70ºF.

The 100 ml of product from bottle A was combined in an IV bag of saline, and then 100 ml of product from bottle B was combined in an IV bag.

Bag IV was hung from an elevation point, 18 ”above the infusion point.

A catheter was inserted into the subject's jugular vein.

Pre-treatment venous blood samples were taken from the patient for IDEXX analysis (hematology, chemistry, endocrinology and serology) and blood gas analysis (acid / base status, oximetry, electrolytes, metabolites) (T = -5 min). Five minutes (T = O min) later, the IV bag was connected to a catheter, and the drip was opened to start the infusion.

Forty-five minutes (T = 45 min) later, the drip rate was adjusted to complete the infusion.

Samples of venous blood were taken from the subject during treatment, 15 minutes (T = 15 min) and 30 minutes (T = 30 min) after the start of treatment.

The post-treatment venous blood samples were extracted 60 minutes (T = 60 min) and 120 minutes (T = 120 min) after the start of treatment.

The post-treatment samples were submitted to gas analysis (acid / base status, oximetry, electrolytes and metabolites)

* Note: Subject 1 "pretreatment" venous blood samples for IDEXX analysis (hematology, chemistry, endocrinology and serology) were mistakenly sampled 60 minutes after treatment started.

The results probably reflect post-dose changes in plasma volume, as large changes were observed in the concentration-based markers (eg, RBC, hematocrit).

RESULTS Results Section 1: Blood Response gWGás and Acid-Base:

[00137] Subject 2 Dose 1 AS and Doses 4 and 5 ASVM - Observed Response: blood pH, HCO3- and blood oximetry were observed at intervals of 5 min before the initial dose (T = -5), 20 min after the start of the dose (T = 20), and minutes after the completion of the dose (full dose at T = 45, measurement at T = 50) as shown in Table 8. Table 8. Subject 2 Response to Dose 1 AS, Dose 4 ASVM, Dose 5 ASVM

ASVM ASVM | time min and 2 o ps 2 PH 1 7.392 1 7.437 1 7.431 [7.350 1 7.416 1 7.394 [7.453 17,426 1 7.417 cHCco3- | mmol / 1 | 33.2 131.0 131.0 [26.7 126.4 126.6 29.4 127.8 127.3 po2 í mmHg 30 i 34 í 35 24 í 39 í 31 37 í 39 í 33 so2 1 55 167 1 69 39 1176 159 73 176 1 66

[00138] Subject 2 -—- Observed Response for Dose 1 AS: As shown in Figure 6, it was observed that the venous pH increased from a borderline acid start by 7.392, towards alkaline at T = 20, and then decreased by towards acid at T = 50. Although the AS solution should change the bloodstream to acid, this was not observed, perhaps because the observation point at T = 20 occurred after the process of renal compensation had already started state management acid-base. At the same time, venous HCO3 was measured for the first time to have a high value of 33.2 mmol / l,

consistent with Cushing's disease. During treatment, the values reduced to 31 mmol / l at the other time points, consistent with a flow for intracellular or renal extraction. As shown in Figure 7, an increase in sO ;, and venous pOr was observed during this period, from the initial low levels of 55% sO7 and 30 mm Hg pO », consistent with improved oxygen service in the tissues. It was observed that pcOr decreased, consistent with a reduction in metabolism, expansion of plasma volume, or reduced hemoglobin affinity for CO7, with increased affinity for O..

[00139] Subject 2 - Observed Response for Dose 4 ASVM: As shown in Figure 8, it was observed that the venous pH increased in the alkaline direction at T = 20, and then returned to acid at T = 50, in a response that was similar to Dose 1, using AS. At the same time, venous HCO3 was observed at T = -5 as 26.7 mmol / l, consistent with a Cushing's resolution, and virtually unchanged during the observation period. As shown in Figure 9, it was again observed that sO ;, and venous pOr increased during drug administration, along with a reduction in pCOz2.

[00140] Subject 2 - Observed Response for Dose 5 ASVM: As shown in Figure 10, dose 5 elicited a different response from doses 1 and 4, in which the venous pH was reduced to acid during the observation period. This can be attributed to the more alkaline tendency of the bloodstream. At the same time, venous HCO3 was observed at T = -5 with 29.4 mmol / l, again consistent with a Cushing resolution. Rather than increasing or remaining unchanged, HCO3z- the blood stream decreased during the observation period, consistent with intracellular flow. As shown in Figure 11, sO7, and pO ;, venous were observed with levels higher than the initial 73% sO; and 37 mmHg pO ,, constant with a more durable restoration of the improved oxygen service to the tissues. It was again observed that sO, and pOr increased even further during drug administration. PCO; r remained virtually unchanged. The difference in behavior at dose 5, in relation to doses 1 and 4, is consistent with obtaining an improved homeostasis in relation to the acid / base state.

[00141] Subject 3 Doses 1 and 4 ASVM and Dose 5 AS - Observed Response: Blood pH, blood HCO3- and oximetry were observed at intervals of 5 min before the dose started (T = -5), 20 min after the start of the dose (T = 20), and minutes after the completion of the dose (full dose at T = 45, measurement at T = 50) as shown in Table 5.

[00142] Subject 3 Doses 1 and 4 ASVM and Dose 5 AS - Observed Response: Blood pH, blood HCO3- and oximetry were observed at a time interval of 5 min before the dose started (T = -5), 20 min after the starting dose (T = 20), and 5 minutes after the completion of the dose (full dose at T = 45, measured at T = 50) as shown in Table 9.

Table 9: Subject 3 Response to Dose 1 and 4 ASVM, Dose

AT

ASVM ASVM AS pp EEE PH i - 7.455 i * i * 7.437 17,392 17.428 7.423 i 7.412 1.375 cHCo3- | mmo1 / 1 32.5 Ds Ds 27.1 127.3 Drn7 26.2 126.0 25.5 pco2 i mmHg 46.2 D + D + 42.6 149.9 145.0 42.4 143.6 149.9 po2 mig 29 - - 32 29 E) 34 EE only? iz 57 Ds - 67 iso 169 70 te E i À À i À À À * Sample not available

[00143] Subject 3 - Observed Response for Doses 1, 4 ASVM: Not shown, materially similar to Subject 2.

[00144] Subject 3 - Observed Response for Dose 5 AS: As shown in Figure 12, dose 5 elicited a response similar to dose 5 applied to Subject 2, in which the venous pH was observed that reduced to acid during the period of Note. At the same time, venous HCO3 was observed at T = -5 as 27.7 mmol / l, again consistent with Cushing's resolution. Instead of increasing or remaining unchanged, HCO3- in the blood stream decreased during the observation period, consistent with flow into the intracellular. As shown in Figure 13, sO; and venous pOr were observed to have relatively high onset levels at 70% sO, and 34 mm Hg pOr, consistent with a tendency to improve oxygen service to tissues, compared to pre-treatment levels. In contrast to the response to Dose 5 of Subject 2, using the product AS, sO; eOr responds to the infusion of the AS product, dripping during the administration of the drug, which is a recognized stimulus for having the potential to stimulate EPO release from the liver to promote RBC storage supplementation. This difference in response may have been caused by differences in formulation between the AS and ASVM configurations. PCOr increased correspondingly during that period.

[00145] Subject 1 Dose data 1, 4, 5 ASVM (Shown to completely, Similar to Subject 2 and Subject 3): blood pH, blood HCO3- and oximetry were observed at 5 min time intervals before dose start (T = -5), min after the dose starts (T = 20), and 5 minutes after completion of the dose (complete dose at T = 45, mediation at T = 50) as shown in Table 10. Table 10: Subject 1 Response to Dose 1, 4, 5 ASVM

ASVM ASVM ASVM

FE E EEA EEE AE PA 1- 7.4441 * 1 * [7,42617,43517,448 7,429 17,447 17,431 shards- | mmo1 / 1 34.1 fx is 30.1 31.1 131.3 30.1 129.9 129.6 pco2 | mig 49.7 bs ”50.8 150.5 148.5 49.6 145.8 a77 po2 | papaya 30 i * Í * [24 i 29 i 35 36 i 37 i 36 Result of Section 2: Electrolyte, Hb, Glu and Lac Response:

[00146] Subject 2 Dose 1 AS and Doses 4 and 5 ASVM - Observed Response: blood electrolytes, hemoglobin (Hb), Glucose (Glu) and Lactate (Lac) were observed at intervals of 5 min before the start of the dose (T = -5), 20 min after starting the dose (T = 20), and 5 minutes after completing the dose (full dose at T = 45, mediation at T = 50) as shown in Table 11. Table 11: Subject 2 Response to Dose 4, 5 ASVM

ASVM ASVM FF EEE AA

EE EEE E rar E EO

[00147] Subject 2 Doses 4 and 5 ASVM - Observed Hb Response and Inference of Changes in Plasma Volume: During the observation period, Hb decreased from its initial value, sometimes showing evidence of recovery during the observation period. This cannot be interpreted as hemolysis, as a recovery on that time scale would be impossible. The change in Hb concentration is consistent with a change in blood volume, probably due to a change in plasma volume. This change is necessary during the stimulation of the exercise type to maintain vascular pressure, under conditions of vasodilation, where the vascular volume increases.

[00148] Subject 2 Doses 4 and 5 ASVM - Observed Glucose Response: During the observation period, Glucose was irregular (up and down) from its initial value, while showing evidence of recovery during the observation period . Although the reduction can be attributed to the increase in blood volume, increases in the concentration of Glucose cannot. The observed elevation of Glucose is consistent with the irregularity of the glucose change, such as occurred during exercise.

[00149] Subject 2 ASVM Doses 4 and 5 - Observed Lactate Response: During the observation period, it was observed that Lactate had a low value, which further reduced in Dose 4, and increased slightly in Dose 5. That is consistent with the lactate load that dropped constantly with successive doses, as the perfusion improved, increased aerobic metabolism, in order to resolve the lack of lactate. Elevated lactate was observed at dose 5, despite the suspicion of dilution of plasma volume. This is consistent with the presentation of HCO3- in the muscles to release the stored lactate.

[00150] Subject 2 Doses 4 and 5 ASVM - Response Observed in Electrolytes: During the observation period, alteration of electrolytes was observed. It was observed that Potassium and Sodium decreased during treatment, which can be attributed to the increase in plasma volume. Which is consistent with a flow of H 'in the cell, raising the chemosmotic gradient to improve ATP yield and increasing the action of Na / K ATPase to transport K' to the cell. At the same time, a reduction in calcium was observed in the bloodstream. The change in H '/ Na *' and change in K + / Na + t promoted an elevation of Na 'in the bloodstream, to promote the change in Ca ”in the blood through the change in Caº? * / Na *. Elevations of Cl ”in the bloodstream were also noticed during the observation period.

[00151] Results Section 4: Hematology, Chemistry, Endocrinology and Serology:

[00152] Response Observed between Day 1 and Day 8 covering 4 doses in 3 horses: Hematology, Chemistry, Endocrinology and Serology were observed on day 1, before Dose 1, and on Day 8, before dose 5, thus encompassing 4 doses of ASVM, or in some cases AS dose. The following effects can be seen in the data, as shown in Table 12.

* It was observed that the count of white blood cells (WBC - White Blood Cell) and neutrophils decreased in all subjects, consistent with a relief of the response to inflammation.

* An increase in the platelet and fibrinogen count was observed for all subjects, consistent with the control over the coagulation cascade and reduced consumption of coagulation products. It is also consistent with increased production of platelets in the bone marrow after resolution of thrombocytopenia and increased presentation of fibrinogen by improving liver function.

* It was observed that creatinine increased in all subjects, consistent with an increase in muscle mass and an increase in the ability to store ATP in the muscle as phosphocreatine.

* BUN: It was observed that the creatinine ratio dropped for all subjects, consistent with the increased flow through the kidneys.

* Ca * and K 'drop was observed for all subjects, consistent with K' intracellular capacitation via Na * / K * ATPase and renal Ca? * Extraction ”, in order to reduce blood flow presentation. Reductions in Ca ** and increase in K 'may have the potential to reduce the dependence of the chemosmotic gradient on Caº', in order to restore the transport function of the electron chain, reduce corresponding ROS for the transport of the electron chain, and increase the basal metabolic rate. A reduction in intracellular calcium, together with reduced ROS and alkaline conditions and elevated Mg? *, Would also have the potential to improve the function of the peroxisome to restore the reduction of long-chain fatty acids for metabolic use, increased ability to repair myelin. to improve nerve function, and improve the peroxisome's catalase service. Additionally, the lower Ca? ** could restore eNOS function by reducing Caveolin bound to cavolae to allow eNOS to translocate the Golgi back into the caveola membranes. Lower intracellular calcium may also signal more M2 phenotype presentation for macrophages, microglia and osteoblasts, among others. The increase in K * '* could act to improve muscle function and nerve transmission, reduce muscle cramps and provide other benefits.

* e It was observed that creatine kinase decreased in all subjects, consistent with a potential increase in consumption of creatine kinase in enzymatic action to promote the storage of ATP with creatine as phosphocreatine to increase the energy stored in the muscles. Alternatively, the reduction in blood plasma may indicate a reduction in the continuous rate of tissue damage, such as in myocardial infarction (heart attack), rhabdomyolysis (severe muscle rupture), muscle dystrophy, autoimmune myositis, and acute kidney injury, from to minimize the presentation of damaged tissue content to the bloodstream.

* It was observed that the total T4 increased for all subjects, potentially indicating an improved thyroid function to produce more thyroxine. This, among other things, is associated with an increase in the synthesis of Na '/ K' ATPases, glucose absorption, glycogenolysis, gluconeogenesis, lipolysis, protein synthesis, liquid catabolic degradation, beta-l cardiac receptors to improve system control sympathetic nervous system and basal metabolic rate.

and It was observed that endogenous equine ACTH dropped for all subjects, consistent with a reduction in cortisol levels, in order to promote calming and anti-anxiety effects. Additionally, it is consistent with promoting the resolution of Cushing's disease.

and Lyme antibodies have been shown to decrease in the ratio display, as indicated by a smaller divider. This is consistent with the resolution of Lyme disease and the progression towards quiescent immunity, with reduced response to inflammation.

* It was observed that Lyme proteins increased in presentation, consistent with the appropriate action of plasmin during the alkaline recovery phases, which can reduce the fibrin layer associated with borrelia, in order to expose its surface proteins.

Table 12: Hematology, Chemistry, Endocrinology and Serology Evolving in more than 4 doses in 7 days s Test 14- 21- 14- 21- 14- 21- Nov Nov Nov Nov Nov Nov HEMATOLOGY Pre Post | Pre Pre Pre Pre Amost | Amost | Amost | Amost | Amost | Amost WEC 6.1 7.8 7.2 8.9 9.0 4.3- 11.4k / u! Neutrophils 3.25 2.275 [3.962 [3.168 | 3,382 | 4.329 | 2.46-723K / ul [FERE | and 6 1 [1 [156 [7050/41 ibrinogens 116 127 129 168 131 147 135- 249mg / dl a | Creatine 0.7 1.2 1.4 1.2 1.4 0.8- 1.8mg / dl BUN: Creatine 30.0 [23.3 [10.8 [10.0 [11.7 [7, 9 Calcium ratio 13.0 [11.6 [12.4 | 11.6 [12.2 [11.6 [102 12.8mg / dl Sodium 136 136 136 137 136 137 132- 141mmol / l Potassium 4.1 5 , 2 3.7 5.4 3.9 2.5 - 5.2 mmol / | Creatine 334 221 271 210 349 259 130-497U / | Kinase

ENDOCRINOLOG

IA BE | [25 [17 25 5 77 26 [Ba [Essósenos [as [26 a me 36 36 [osspem

Equine

ACTE if TT AT AAA Lym and Post [Post | Posê | Posê | Posê | Posel Antibody 1: 320 | 1: 800 | 1: 800 | [1: 200 | 1: 800 | : 200 by IFA o Lym and OspA 123 129 197 242 225 201 neg neg neg neg neg neg Lym and OspC 73 77 238 272 79 69 neg neg neg neg neg Lym and OspF b2 3000 3963 318 390 464 498 pos neg neg neg neg Antibody c2 Neg Pos Neg Neg Neg Neg Ehrichia canis Notes: a3 - Significant variations in endogenous ACTH concentration associated with the time that was reported. An endogenous ACTH measurement between November and July of> 35pg / ml is consistent with equine Cushing's disease (PPID). Cases that start early, PPID may fail to demonstrate a significant increase in resting ACTH concentration during these months. It is recommended to retest ACTH levels at rest during August and October, when the sensitivity test is very high, or a TRH stimulus test (December to June). Between August and October, an endogenous ACTH concentration of> 100pg / ml is consistent with equine Cushing's disease. a4 - Interpretation: If your result is negative, the interpretation is “No antibody present € 1: 100”; positive and (title), the interpretation is “Antibody present (& (title).” b2 - Cornell no longer offers the Lyme Western Blot test. The Multiplex Equine Lyme is offered instead.

Equine Lyme Disease - Multiplex: The Equine Multiplex assay determines antibodies to three antigens, called B. burgdorferi outer surface protein (Osp) that have been shown to correlate with vaccine antibodies, or acute and chronic stage of Lyme disease.

Negative: Negative values for antibodies to all three Osp antigens are predictive that the horse is not infected.

If only one or two values are in the negative range, see interpretation as equivocal or positive values for the corresponding Osp antigen.

Misconception: Equivocal values may indicate early infection or may be induced by non-specific serum reactions.

If there are no positive values for any of the three Osp antigens, the horse should be retested in 2-3 weeks to confirm or exclude early infection.

If one or two values in the positive range show interpretation for positive values for that corresponding Osp antigen.

Positive / OspA (> 2000): Positive values for antibodies to OspA are typically seen in vaccinated animals.

In horses, however, antibodies to OspA are also seen to rise during infection.

Thus the interpretation in the antibody results for OspA is more complex in horses.

If antibodies to OspA are positive, along with OspA, the horse can be considered as infected with burgdorferi B.

Positive / OspC (> 1000): Positive values for antibodies to Ospc are only indicative for early infection.

Antibody values for OspA may also be elevated during early infection.

Positive / OspF (> 1250): Positive values for antibodies to OsprfF are only predictive for the stage of chronic infection.

Positive values for antibodies to OspC and OspF in the same sample are indicative for an infection that occurred several weeks ago and is heading towards a chronic stage.

Reference test performed at Cornell University. c2 - Interpretation: If your result is: NEGATIVE Without the presence of anticorpot1: 25; POSITIVE ((title) Antibody presentet (title). Positive samples are tested in incremental dilutions to 1: 3200. Titles beyond 1: 3200 are usually of the limit clinical value.

If you want an end point title, there is an additional charge.

A positive titer indicates exposure to E. canis or similar antigens, but does not confirm the presence of the disease.

A CBC is recommended to identify abnormalities consistent with infections.

If confirmation of infection is desired, Ehrlichia PCR test, code 2634 may be useful, specifically in clinically ill animals.

Claims (54)

1. Stable therapeutic composition formulated for intravenous administration to an individual, comprising an intravenous buffer solution, comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffer agent in a sterile aqueous solution, characterized by: the concentration of pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acidity content of 60 mmol / l1 to 3,000 mmol / l when administered to an individual, and the selection of pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a pH buffer solution between 4 and 7.7. 2. Composition according to claim Error! Reference source not found., Characterized by: the pharmaceutical grade acid is hydrochloric acid, ascorbic acid, acetic acid, (other physiologically acceptable acids), or a combination thereof. 3. Composition according to claim Error! Reference source not found., Characterized by: at least the pH buffering agent is sodium bicarbonate, a phosphate buffer, sodium hydroxide, organic acid, organic amine, ammonia, citrate buffer, a synthetic buffer that creates alkaline conditions specific (eg, trishydroxymethyl amino methane), (other physiologically acceptable buffers), or a combination thereof. 4, Composition according to claim Error! Reference source not found., Additionally comprising one or more ingredients selected from the group consisting of vitamins, salts, acids, amino acids or salts thereof, and stabilized oxidizing species. A composition according to claim 4, further comprising ascorbic acid. A composition according to claim 4, further comprising dehydroascorbic acid. A composition according to claim 4, further comprising other recognized antioxidant defense compounds, including non-enzymatic compounds, such as tocopherol (aTCP), coenzyme Q10 (9Q) cytochrome c (C) and glutathione (GSH) and enzymatic components, including manganese superoxide dismutase (MNSOD), catalase (Cat), glutathione peroxidase (GPX) glutathione peroxidase phospholipid hydroperoxide (PGPX), glutathione reductase (GR); peroxiredoxins (PRX3 / 5), glutaredoxin (GRX2), thioredoxin (TRX2) and thioredoxin reductase (TRXR2). A composition according to claim 4, further comprising one or more of a sodium salt, a magnesium salt, a potassium salt and a calcium salt. A composition according to claim 4, comprising - “additionally one or more vitamin B, vitamin C and vitamin K. Composition according to claim 1, characterized in that the composition is formulated for intravenous, bolus, dermal, oral, optical, suppository, buccal, ocular or inhalation administration. Composition according to claim 1, characterized in that: the composition is formulated as a topical liquid, gel or paste. Composition according to claim 1, characterized in that: the composition is formulated for ocular administration in the form of eye drops. 13. Composition according to claim 4, formulated in hypotonic, isotonic or hypertonic form. 14. Composition according to claim Error! Reference source not found, characterized by: intravenous administration is a bolus delivery. 15. Composition according to claim Error! Reference source not found, characterized by: the composition is freeze-dried or frozen. 16. Composition according to claim Error! Reference source not found, characterized by: the composition is stored in a spectral blocking vial. 17. Composition according to claim Error! Reference source not found., Characterized by: composition be formed by combining components from two or more vials. 18. Stable therapeutic composition formulated for intravenous administration to an individual, comprising pharmaceutical grade: 900 + 90 mg of L-Ascorbic acid; 63.33 + 6.33 mg Thiamine HCl; 808 + 80.8 mg of magnesium sulfate; 1.93 + 0.193 mg of Cyanocobalamin; 119 + 11.9 mg of Niacinamide; 119 + 11.9 mg of Pyridoxine HCl; 2.53 t + 0.253 mg Riboflavin 5'Phosphate; 2.93 + 0.293 mg of D-Calcium Pantothenate; 840 + 84 mg of sodium bicarbonate; 4.5 + 0.45 mM HCl; and water in quantity to obtain a final volume of the composition of 20 ml. A composition according to claim 18, comprising - additionally 100 + 10 mg of dehydroascorbic acid. 20. Method of treating or ameliorating acidosis in an individual, the method comprising administering to the individual the stable therapeutic composition, comprising an intravenous buffer solution, comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffer agent in a sterile aqueous solution, characterized by: the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acidity content of 60 mmol / l1 to 3,000 mmol / l when administered to an individual, and the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution of pH between 4 and 7.7. 21. Method of treating or ameliorating excess base in an individual, the method comprising administering to the individual a stable therapeutic composition, comprising an intravenous buffer solution, comprising at least one pharmaceutical grade acid and at least one buffering agent. Pharmaceutical grade pH in a sterile aqueous solution, characterized by: the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acidity content of 60 mmol / 1 to 3,000 mmol / l when administered to an individual, and the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective in providing a buffer solution of pH between 4 and 7.7. 22. Method of elevating oxygen in the blood in an individual, the method comprising administering to the individual a stable therapeutic composition, comprising an intravenous buffer solution, comprising at least one pharmaceutical grade acid and at least one pH buffering agent of pharmaceutical grade in a sterile aqueous solution, characterized by: the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acidity content of 60 mmol / l1 to 3,000 mmol / l when administered to an individual, and the selection of the acid pharmaceutical grade and the pharmaceutical grade pH buffering agent is effective in providing a pH buffer solution between 4 and 7.7. 23. The method of claim 22, wherein: the method comprises raising the pO2 in venous blood in an individual. 24. Method of treating or ameliorating a mitochondrial disorder, metabolic disorder, a condition associated with diabetes or cardiovascular dysfunction in an individual in need thereof, the method comprises administering to the individual a stable therapeutic composition, comprising an intravenous buffer solution, comprising at least at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffer agent and a sterile aqueous solution, characterized in that: the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffer agent in the buffer solution is sufficient to provide a total acid content of 60 mmol / l to 3,000 mmol / l when administered to an individual, and the selection of pharmaceutical grade acid and pharmaceutical grade pH buffering agent is effective in providing a buffer solution of pH between 4 and 7, 7. 25. The method of claim 24, characterized in that: the metabolic disorder is diabetes, insulin resistant, glucose intolerant, hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia or hyperlipoproteinemia. 26. The method of claim 24, wherein: the condition associated with diabetes is hypertension, hyperlipidemia, hyperlipoproteinemia, nephropathy, neuropathy, renal failure, retinopathy, diabetic ulcer, cataract, insulin resistance syndrome and cachexia. 27. Method according to claim 24, characterized in that: the cardiovascular dysfunction is coronary heart disease, cerebrovascular disease, hypertension, peripheral arterial disease, occlusive arterial disease, angina, rheumatic heart disease, congenital heart disease, heart failure, heart failure, palpitations, supraventricular tachycardia fibrillation, fainting, dizziness, fatigue, migraine, high levels of total blood cholesterol and / or LDL cholesterol, low level of HDL cholesterol, high level of lipoprotein, heart infections such as carditis and endocarditis, diabetic ulcer , thrombophlebitis, Raynaud's disease, anorexia nervosa, lameness, gangrene, atherosclerosis and peripheral artery disease. 28. The method of claim 24, characterized in that: the mitochondrial disorder is a neurodegenerative disorder, a cardiovascular disease, a metabolic syndrome, an autoimmune disease, a neurobehavioral or psychiatric disease, a gastrointestinal disorder, a stressful disease, a musculoskeletal disease chronic or a chronic infection. 29. The method of claim 24, wherein: the composition comprises - additionally dehydroascorbic acid. 30. The method of claim 24, further comprising one or more source of magnesium ions, a source of potassium ions and a source of calcium ions. 31. The method of claim 24, further comprising one or more of a vitamin B, vitamin C and vitamin K. 32. The method of claim 24, further comprising other recognized antioxidant defense compounds, including non-enzymatic compounds, such as tocopherol (aTCP), coenzymes Q10 (Q), cytochrome c (C) and glutathione (GSH) and enzyme components including manganese superoxide dismutase (MnSOD), catalase (Cat), glutathione peroxidase (GPX), glutathione peroxidase phospholipid hydroperoxide (PGPX), glutathione reductase (GR); ; peroxiredoxins (PRX3 / 5), glutaredoxin (GRX2), thioredoxin (TRX2) and thioredoxin reductase (TRXR2). 33. Method according to claim 24, formulated in hypotonic, isotonic or hypertonic form. 34. The method of claim 24, wherein: the composition is administered intravenously, in bolus, dermally, orally, optically, via suppository, buccally or via inhalation. 35. The method of claim 24, wherein: said administration comprises introducing said composition by infusion over a period of time from about 1 minute to about 1 hour and said infusion being repeated as necessary over a period of selected time from about 1 day to about 1 year. 36. Method for modifying an individual's metabolism, the method comprises administering to the individual a stable therapeutic composition, comprising an intravenous buffer solution, comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffer agent in a solution sterile aqueous solution, characterized by: the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acidity content of 60 mmol / 1 to 3,000 mmol / l1 when administered to an individual , and the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a buffer solution of pH between 4 and 7.7. 37. Method of treating a central nervous system disorder in an individual in need thereof, the method comprising administering to the individual a stable therapeutic composition, comprising an intravenous buffer solution, comprising at least one pharmaceutical grade acid and at least one agent pharmaceutical grade pH buffer in a sterile aqueous solution, characterized by: the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acidity content of 60 mmol / l1 to 3,000 mmol / l when administered to an individual, and the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective in providing a buffer solution of pH between 4 and 7.7. 38. A method for treating an individual's chronic wounds, the method comprising administering to the individual a stable therapeutic composition, comprising an intravenous buffer solution, comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffer agent in one sterile aqueous solution, characterized by: the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acidity content of 60 mmol / 1 to 3,000 mmol / 1 when administered to a individual, and the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective to provide a pH buffer solution between 4 and 7.7. 39. Method for improving an individual's mental or physical performance, the method comprising administering to the individual a stable therapeutic composition, comprising an intravenous buffer solution, comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffer agent in a sterile aqueous solution, characterized by: the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acidity content of 60 mmol / 1 to 3,000 mmol / 1 when administered to an individual, and the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective in providing a buffer solution of pH between 4 and 7.7. 40. Method for reducing the lactate load in an individual in need thereof, the method comprises administering to the individual a stable therapeutic composition, comprising an intravenous buffer solution, comprising at least one pharmaceutical grade acid and at least one pH buffering agent pharmaceutical grade in a sterile aqueous solution, characterized by: the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acidity content of 60 mmol / 1 to 3,000 mmol / , when administered to an individual, and the selection of pharmaceutical grade acid and pharmaceutical grade pH buffering agent is effective in providing a buffer solution of pH between 4 and 7.7. 41. Method according to claim 40, characterized in that: the lactate load is acidosis, sepsis or multiple system atrophy (MAS - Multiple System Atrophy) 42. The method of claim 40, characterized in that: the lactate load is the result of physical effort. 43. Method for resolving or ameliorating hypoxic stress in an individual in need thereof, the method comprising administering to the individual a stable therapeutic composition, comprising an intravenous buffer solution, comprising at least one pharmaceutical grade acid and at least one buffering agent. Pharmaceutical grade pH in a sterile aqueous solution, characterized by: the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acidity content of 60 mmol / l1 to 3,000 mmol / l when administered to an individual, and the selection of pharmaceutical grade acid and pharmaceutical grade pH buffering agent is effective in providing a buffer solution of pH between 4 and 7.7. 44, Method for removing vascular plaque from an individual's arteries and thus resolving the metabolic crisis resulting from Caº accumulation *, the method comprising administering to the individual a stable therapeutic composition, comprising an intravenous buffer solution, comprising at least one acid of pharmaceutical grade and at least one pharmaceutical grade pH buffering agent in a sterile aqueous solution, characterized in that: the concentration of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total acidity content titratable from 60 mmol / 1 to 3,000 mmol / 1 when administered to an individual, and the selection of the pharmaceutical grade acid and the pharmaceutical grade pH buffering agent is effective in providing a pH buffer solution of 4 and 7.7. 45. The method of any one of claims 20-44, characterized in that: the individual is a human or veterinary individual. 46. The method of any one of claims 20-44, characterized in that: the buffer solution is sufficient to reduce the physiological pH of an individual's bloodstream from 0.01 to 1.1. 47. The method of claim 46, characterized in that: the buffer solution has a buffering capacity sufficient to sustain a reduction in the physiological pH of the individual's bloodstream between 1 minute and 1 week. 48. The method of claim 46, characterized in that: the buffer solution is sufficient to reduce the physiological pH of an individual's bloodstream from 0.15 to 0.75. 49, Method according to claim 46, characterized in that: the buffer solution is sufficient to reduce the physiological pH of an individual's bloodstream from 0.15 to 0.5. 50. The method of claim 46, characterized in that: the buffer solution has a sufficient buffering capacity to sustain the reduction of the physiological pH of the individual's bloodstream between 1 minute and 1 hour. 51. The method of claim 46, characterized in that: the buffer solution has a sufficient buffering capacity to sustain a reduction in the physiological pH of the individual's bloodstream between 1 hour and 11 days. 52. The method of claim 46, characterized in that: the buffer solution has a sufficient buffering capacity to sustain the reduction of the physiological pH of the individual's bloodstream for between 1 day and the week. 53. Kit comprising: a. A first flask, containing a stable therapeutic composition, comprising an intravenous buffer solution, comprising at least one pharmaceutical grade acid and at least one pharmaceutical grade pH buffer agent in a sterile aqueous solution, characterized by: the concentration of the acid grade and the pharmaceutical grade pH buffering agent in the buffer solution is sufficient to provide a total titratable acidity content of 60 mmol / 1 at 3,000 mmol / 1 when administered to an individual, and the selection of pharmaceutical grade acid and pharmaceutical grade pH buffering agent is effective in providing a buffer solution of pH between 4 and 7.7; and b. Instructions for use. 54. Kit comprising: a. a first vial, containing an intravenous buffer solution, comprising at least one pharmaceutical grade acid in a sterile aqueous solution, and b. a second vial, containing at least one pharmaceutical grade pH buffering agent in a sterile aqueous solution, characterized by: when combined, the contents of the two vials form an intravenous buffering solution, in which the concentration of the pharmaceutical grade acid and the agent Pharmaceutical grade pH buffer in the buffer solution is sufficient to provide a total titratable acidity content of 60 mmol / 1 at 3,000 mmol / 1 when administered to an individual, and the selection of pharmaceutical grade acid and pharmaceutical grade pH buffering agent is effective in providing a pH buffer solution between 4 and 7.7; and c. instructions for use.